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Cancers
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Apoptosis in Cancer
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Apoptosis in Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 August 2019) | Viewed by 129052

Special Issue Editor

Prof. Dr. Arun Dharmarajan

E-Mail Website1 Website2
Guest Editor
1. School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA, Australia
2. Department of Biomedical Sciences, Faculty of Biomedical Sciences, Technology and Research, Sriramachandra Institute of Higher Education and Research, Chennai, India
3. School of Human Sciences, The University of Western Australia, Nedlands, Perth, WA 6009, Australia
Interests: Wnt signaling; secreted frizzled related protein 4; cancer; cancer stem cells; angiogenesis; apoptosis; redox signaling; molecular modeling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the last decade, basic cancer research has produced remarkable advances in our understanding of cancer biology and cancer genetics. Among the most important of these advances is the realization that apoptosis and the genes that control it have a profound effect on the malignant phenotype. For example, it is now clear some oncogenic mutations disrupt the apoptotic process leading to tumor initiation, progression, and finally metastasis. It is now well documented that most cytotoxic anticancer agents induce apoptosis, raising the intriguing possibility that deregulation in apoptotic programs contributes to treatment failure. Apoptosis is mechanistically governed through two main pathways; the extrinsic (death receptor-mediated) and the intrinsic, or the mitochondrial pathway which is activated in response to cellular damage induced through radiation, hypoxia, and some anti-cancer agents. Dysregulation of these apoptotic pathways can result in the resistance of cell death, and is a hallmark of cancer. Consequently, targeting key regulatory proteins within these pathways has been a primary focus of many cancer studies. A prototypical example of this is the targeting of B-cell lymphoma 2 (BCL-2) family of proteins. The primary focus of this topic will be cell signaling in apoptosis, mitochondrial-mediated apoptosis, novel compounds to target apoptosis and cancer. In addition, the reviews and research articles will explore the mechanisms of apoptosis and the ways in which tumor cells modulate these processes to induce their survival and examine current clinical modalities aimed at exploiting these defects to selectively induce apoptosis in tumor cells.

Prof. Arun Dharmarajan
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Apoptosis
  • Cancer
  • Redox signaling
  • Wnt
  • Oncogenes
  • Frizzled

Published Papers (23 papers)

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Research

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18 pages, 3574 KiB  
Article
Galeterone and The Next Generation Galeterone Analogs, VNPP414 and VNPP433-3β Exert Potent Therapeutic Effects in Castration-/Drug-Resistant Prostate Cancer Preclinical Models In Vitro and In Vivo
by Andrew K. Kwegyir-Afful, Senthilmurugan Ramalingam, Vidya P. Ramamurthy, Puranik Purushottamachar, Francis N. Murigi, Tadas S. Vasaitis, Weiliang Huang, Maureen A. Kane, Yuji Zhang, Nicholas Ambulos, Sudhir Tiwari, Pratima Srivastava, Ivo P. Nnane, Arif Hussain, Yun Qiu, David J. Weber and Vincent C. O. Njar
Cancers 2019, 11(11), 1637; https://doi.org/10.3390/cancers11111637 - 24 Oct 2019
Cited by 21 | Viewed by 4568
Abstract
These studies compared the efficacies of our clinical agent galeterone (Gal) and the FDA-approved prostate cancer drug, enzalutamide (ENZ) with two lead next generation galeterone analogs (NGGAs), VNPP414 and VNPP433-3β, using prostate cancer (PC) in vitro and in vivo models. Antitumor activities of [...] Read more.
These studies compared the efficacies of our clinical agent galeterone (Gal) and the FDA-approved prostate cancer drug, enzalutamide (ENZ) with two lead next generation galeterone analogs (NGGAs), VNPP414 and VNPP433-3β, using prostate cancer (PC) in vitro and in vivo models. Antitumor activities of orally administered agents were also assessed in CWR22Rv1 tumor-bearing mice. We demonstrated that Gal and NGGAs degraded AR/AR-V7 and Mnk1/2; blocked cell cycle progression and proliferation of human PC cells; induced apoptosis; inhibited cell migration, invasion, and putative stem cell markers; and reversed the expression of epithelial-to-mesenchymal transition (EMT). In addition, Gal/NGGAs (alone or in combination) also inhibited the growth of ENZ-, docetaxel-, and mitoxantrone-resistant human PC cell lines. The NGGAs exhibited improved pharmacokinetic profiles over Gal in mice. Importantly, in vivo testing showed that VNPP433-3β (at 7.53-fold lower equimolar dose than Gal) markedly suppressed (84% vs. Gal, 47%; p < 0.01) the growth of castration-resistant PC (CRPC) CWR22Rv1 xenograft tumors, with no apparent host toxicity. ENZ was ineffective in this CRPC xenograft model. In summary, our findings show that targeting AR/AR-V7 and Mnk1/2 for degradation represents an effective therapeutic strategy for PC/CRPC treatment and supports further development of VNPP433-3β towards clinical investigation. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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22 pages, 8750 KiB  
Article
Inhibition of TFF3 Enhances Sensitivity—and Overcomes Acquired Resistance—to Doxorubicin in Estrogen Receptor-Positive Mammary Carcinoma
by Han Ming Poh, Yi Shiou Chiou, Qing Yun Chong, Ru-Mei Chen, Kanchugarakoppal S. Rangappa, Lan Ma, Tao Zhu, Alan Prem Kumar, Vijay Pandey, Basappa, Soo-Chin Lee and Peter E. Lobie
Cancers 2019, 11(10), 1528; https://doi.org/10.3390/cancers11101528 - 10 Oct 2019
Cited by 16 | Viewed by 3259
Abstract
Dose-dependent toxicity and acquired resistance are two major challenges limiting the efficacious treatment of mammary carcinoma (MC) with doxorubicin. Herein, we investigated the function of Trefoil Factor 3 (TFF3) in the sensitivity and acquired resistance of estrogen receptor positive (ER+) MC cells to [...] Read more.
Dose-dependent toxicity and acquired resistance are two major challenges limiting the efficacious treatment of mammary carcinoma (MC) with doxorubicin. Herein, we investigated the function of Trefoil Factor 3 (TFF3) in the sensitivity and acquired resistance of estrogen receptor positive (ER+) MC cells to doxorubicin. Doxorubicin treatment of ER+MC cells increased TFF3 expression. The depletion of TFF3 by siRNA or inhibition with a small molecule TFF3 inhibitor (AMPC) synergistically enhanced the efficacy of doxorubicin in ER+MC through the suppression of doxorubicin-induced AKT activation and enhancement of doxorubicin-induced apoptosis. Elevated expression of TFF3 and increased activation of AKT were also observed using a model of acquired doxorubicin resistance in ER+MC cells. AMPC partially re-sensitized the doxorubicin resistant cells to doxorubicin-induced apoptosis. Indeed, doxorubicin resistant ER + MC cells exhibited increased sensitivity to AMPC as a single agent compared to doxorubicin sensitive cells. In vivo, AMPC attenuated growth of doxorubicin sensitive ER+MC xenografts whereas it produced regression of xenografts generated by doxorubicin resistant ER+MC cells. Hence, TFF3 inhibition may improve the efficacy and reduce required doses of doxorubicin in ER+MC. Moreover, inhibition of TFF3 may also be an effective therapeutic strategy to eradicate doxorubicin resistant ER+MC. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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23 pages, 2668 KiB  
Article
Protein Expression Profiling Identifies Key Proteins and Pathways Involved in Growth Inhibitory Effects Exerted by Guggulsterone in Human Colorectal Cancer Cells
by Rari Leo, Lubna Therachiyil, Sivaraman K. Siveen, Shahab Uddin, Michal Kulinski, Joerg Buddenkotte, Martin Steinhoff and Roopesh Krishnankutty
Cancers 2019, 11(10), 1478; https://doi.org/10.3390/cancers11101478 - 1 Oct 2019
Cited by 16 | Viewed by 4958
Abstract
Colorectal cancer (CRC) is a leading killer cancer worldwide and one of the most common malignancies with increasing incidences of mortality. Guggulsterone (GS) is a plant sterol used for treatment of various ailments such as obesity, hyperlipidemia, diabetes, and arthritis. In the current [...] Read more.
Colorectal cancer (CRC) is a leading killer cancer worldwide and one of the most common malignancies with increasing incidences of mortality. Guggulsterone (GS) is a plant sterol used for treatment of various ailments such as obesity, hyperlipidemia, diabetes, and arthritis. In the current study, anti-cancer effects of GS in human colorectal cancer cell line HCT 116 was tested, potential targets identified using mass spectrometry-based label-free shotgun proteomics approach and key pathways validated by proteome profiler antibody arrays. Comprehensive proteomic profiling identified 14 proteins as significantly dysregulated. Proteins involved in cell proliferation/migration, tumorigenesis, cell growth, metabolism, and DNA replication were downregulated while the protein with functional role in exocytosis/tumor suppression was found to be upregulated. Our study evidenced that GS treatment altered expression of Bcl-2 mediated the mitochondrial release of cytochrome c which triggered the formation of apoptosome as well as activation of caspase-3/7 leading to death of HCT 116 cells via intrinsic apoptosis pathway. GS treatment also induced expression of p53 protein while p21 expression was unaltered with no cell cycle arrest. In addition, GS was found to inhibit NF-kB signaling in colon cancer cells by quelling the expression of its regulated gene products Bcl-2, cIAP-1, and survivin. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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22 pages, 2754 KiB  
Article
Association between PD-1 and PD-L1 Polymorphisms and the Risk of Cancer: A Meta-Analysis of Case-Control Studies
by Mohammad Hashemi, Shima Karami, Sahel Sarabandi, Abdolkarim Moazeni-Roodi, Andrzej Małecki, Saeid Ghavami and Emilia Wiechec
Cancers 2019, 11(8), 1150; https://doi.org/10.3390/cancers11081150 - 10 Aug 2019
Cited by 41 | Viewed by 4463
Abstract
A number of case-control studies regarding the association of the polymorphisms in the programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) genes with the risk of cancer have yielded inconsistent findings. Therefore, we have conducted a comprehensive, updated meta-analysis [...] Read more.
A number of case-control studies regarding the association of the polymorphisms in the programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) genes with the risk of cancer have yielded inconsistent findings. Therefore, we have conducted a comprehensive, updated meta-analysis study to identify the impact of PD-1 and PD-L1 polymorphisms on overall cancer susceptibility. The findings revealed that PD-1 rs2227981 and rs11568821 polymorphisms significantly decreased the overall cancer risk (Odds Ratio (OR) = 0.82, 95% CI = 0.68–0.99, p = 0.04, TT vs. CT+CC; OR = 0.79, 95% CI = 0.67–0.94, p = 0.006, AG vs. GG, and OR = 0.82, 95% CI = 0.70–0.96, p = 0.020, AG+AA vs. GG, respectively), while PD-1 rs7421861 polymorphism significantly increased the risk of developing cancer (OR = 1.16, 95% CI = 1.02–1.33, p = 0.03, CT vs. TT). The PD-L1 rs4143815 variant significantly decreased the risk of cancer in homozygous (OR = 0.62, 95% CI = 0.41–0.94, p = 0.02), dominant (OR = 0.70, 95% CI = 0.50–0.97, p = 0.03), recessive (OR = 0.76, 95% CI = 0.60–0.96, p = 0.02), and allele (OR = 0.78, 95% CI = 0.63–0.96, p = 0.02) genetic models. No significant association between rs2227982, rs36084323, rs10204525, and rs2890658 polymorphisms and overall cancer risk has been found. In conclusions, the results of this meta-analysis have revealed an association between PD-1 rs2227981, rs11568821, rs7421861, as well as PD-L1 rs4143815 polymorphisms and overall cancer susceptibility. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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19 pages, 5052 KiB  
Article
Simvastatin Induces Apoptosis in Medulloblastoma Brain Tumor Cells via Mevalonate Cascade Prenylation Substrates
by Kimia Sheikholeslami, Annan Ali Sher, Sandhini Lockman, Daniel Kroft, Meysam Ganjibakhsh, Kazem Nejati-Koshki, Shahla Shojaei, Saeid Ghavami and Mojgan Rastegar
Cancers 2019, 11(7), 994; https://doi.org/10.3390/cancers11070994 - 17 Jul 2019
Cited by 49 | Viewed by 5327
Abstract
Medulloblastoma is a common pediatric brain tumor and one of the main types of solid cancers in children below the age of 10. Recently, cholesterol-lowering “statin” drugs have been highlighted for their possible anti-cancer effects. Clinically, statins are reported to have promising potential [...] Read more.
Medulloblastoma is a common pediatric brain tumor and one of the main types of solid cancers in children below the age of 10. Recently, cholesterol-lowering “statin” drugs have been highlighted for their possible anti-cancer effects. Clinically, statins are reported to have promising potential for consideration as an adjuvant therapy in different types of cancers. However, the anti-cancer effects of statins in medulloblastoma brain tumor cells are not currently well-defined. Here, we investigated the cell death mechanisms by which simvastatin mediates its effects on different human medulloblastoma cell lines. Simvastatin is a lipophilic drug that inhibits HMG-CoA reductase and has pleotropic effects. Inhibition of HMG-CoA reductase prevents the formation of essential downstream intermediates in the mevalonate cascade, such as farnesyl pyrophosphate (FPP) and gernaylgerany parophosphate (GGPP). These intermediates are involved in the activation pathway of small Rho GTPase proteins in different cell types. We observed that simvastatin significantly induces dose-dependent apoptosis in three different medulloblastoma brain tumor cell lines (Daoy, D283, and D341 cells). Our investigation shows that simvastatin-induced cell death is regulated via prenylation intermediates of the cholesterol metabolism pathway. Our results indicate that the induction of different caspases (caspase 3, 7, 8, and 9) depends on the nature of the medulloblastoma cell line. Western blot analysis shows that simvastatin leads to changes in the expression of regulator proteins involved in apoptosis, such as Bax, Bcl-2, and Bcl-xl. Taken together, our data suggests the potential application of a novel non-classical adjuvant therapy for medulloblastoma, through the regulation of protein prenylation intermediates that occurs via inhibition of the mevalonate pathway. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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17 pages, 3640 KiB  
Article
Furanoic Lipid F-6, A Novel Anti-Cancer Compound that Kills Cancer Cells by Suppressing Proliferation and Inducing Apoptosis
by Jassim M. Al-Hassan, Yuan Fang Liu, Meraj A. Khan, Peiying Yang, Rui Guan, Xiao-Yan Wen, Mohammad Afzal, Sosamma Oommen, Bincy M. Paul, Divya Nair, Nades Palaniyar and Cecil Pace-Asciak
Cancers 2019, 11(7), 960; https://doi.org/10.3390/cancers11070960 - 9 Jul 2019
Cited by 10 | Viewed by 4955
Abstract
Identifying novel anti-cancer drugs is important for devising better cancer treatment options. In a series of studies designed to identify novel therapeutic compounds, we recently showed that a C-20 fatty acid (12,15-epoxy-13,14-dimethyleicosa-12,14-dienoic acid, a furanoic acid or F-6) present in the lipid fraction [...] Read more.
Identifying novel anti-cancer drugs is important for devising better cancer treatment options. In a series of studies designed to identify novel therapeutic compounds, we recently showed that a C-20 fatty acid (12,15-epoxy-13,14-dimethyleicosa-12,14-dienoic acid, a furanoic acid or F-6) present in the lipid fraction of the secretions of the Arabian Gulf catfish skin (Arius bilineatus Val.; AGCS) robustly induces neutrophil extracellular trap formation. Here, we demonstrate that a lipid mix (Ft-3) extracted from AGCS and F-6, a component of Ft-3, dose dependently kill two cancer cell lines (leukemic K-562 and breast MDA MB-231). Pure F-6 is approximately 3.5 to 16 times more effective than Ft-3 in killing these cancer cells, respectively. Multiplex assays and network analyses show that F-6 promotes the activation of MAPKs such as Erk, JNK, and p38, and specifically suppresses JNK-mediated c-Jun activation necessary for AP-1-mediated cell survival pathways. In both cell lines, F-6 suppresses PI3K-Akt-mTOR pathway specific proteins, indicating that cell proliferation and Akt-mediated protection of mitochondrial stability are compromised by this treatment. Western blot analyses of cleaved caspase 3 (cCasp3) and poly ADP ribose polymerase (PARP) confirmed that F-6 dose-dependently induced apoptosis in both of these cell lines. In 14-day cell recovery experiments, cells treated with increasing doses of F-6 and Ft-3 fail to recover after subsequent drug washout. In summary, this study demonstrates that C-20 furanoic acid F-6, suppresses cancer cell proliferation and promotes apoptotic cell death in leukemic and breast cancer cells, and prevents cell recovery. Therefore, F-6 is a potential anti-cancer drug candidate. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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22 pages, 8805 KiB  
Article
Preventing the Solid Cancer Progression via Release of Anticancer-Cytokines in Co-Culture with Cold Plasma-Stimulated Macrophages
by Nagendra Kumar Kaushik, Neha Kaushik, Manish Adhikari, Bhagirath Ghimire, Nguyen Nhat Linh, Yogendra Kumar Mishra, Su-Jae Lee and Eun Ha Choi
Cancers 2019, 11(6), 842; https://doi.org/10.3390/cancers11060842 - 18 Jun 2019
Cited by 54 | Viewed by 7222
Abstract
Non-thermal atmospheric pressure plasma sources operated in ambient environments are known to generate a variety of reactive oxygen and nitrogen species which could be applied for various biomedical applications. Herein, we fabricate a micro-dielectric barrier discharge plasma device by using screen-printing technology and [...] Read more.
Non-thermal atmospheric pressure plasma sources operated in ambient environments are known to generate a variety of reactive oxygen and nitrogen species which could be applied for various biomedical applications. Herein, we fabricate a micro-dielectric barrier discharge plasma device by using screen-printing technology and apply it for studying immuno-stimulatory effects. We demonstrate a tumor-suppressive role for plasma-stimulated macrophages in metastatic solid cancers that directly elicit proliferation and are responsible for tumor relapse mediated by mesenchymal shift. Using microarray analysis, we observed that cold plasma stimulates and differentiates monocyte cells into macrophages as demonstrated by expression of several cytokine/chemokine markers. Moreover, plasma treatment stimulates the differentiation of pro-inflammatory (M1) macrophages to a greater extent. These stimulated macrophages favor anti-tumorigenic immune responses against metastasis acquisition and cancer stem cell maintenance in solid cancers in vitro. Differentiation of monocytes into anticancer macrophages could improve the efficacy of plasma treatment, especially in modifying pro-tumor inflammatory microenvironment through effecting highly resistant immunosuppressive tumor cells associated with tumor relapse. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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20 pages, 6144 KiB  
Article
Antitumor Activity of DFX117 by Dual Inhibition of c-Met and PI3Kα in Non-Small Cell Lung Cancer
by Yanhua Fan, Huaiwei Ding, Donghwa Kim, Duc-Hiep Bach, Ji-Young Hong, Yongnan Xu and Sang Kook Lee
Cancers 2019, 11(5), 627; https://doi.org/10.3390/cancers11050627 - 5 May 2019
Cited by 16 | Viewed by 4947
Abstract
Aberrant activation of hepatocyte growth factor (HGF)/c-Met signaling pathway caused by gene amplification or mutation plays an important role in tumorigenesis. Therefore, c-Met is considered as an attractive target for cancer therapy and c-Met inhibitors have been developed with great interests. However, cancers [...] Read more.
Aberrant activation of hepatocyte growth factor (HGF)/c-Met signaling pathway caused by gene amplification or mutation plays an important role in tumorigenesis. Therefore, c-Met is considered as an attractive target for cancer therapy and c-Met inhibitors have been developed with great interests. However, cancers treated with c-Met inhibitors inevitably develop resistance commonly caused by the activation of PI3K/Akt signal transduction pathway. Therefore, the combination of c-Met and PI3Kα inhibitors showed synergistic activities, especially, in c-Met hyperactivated and PIK3CA-mutated cells. In our previous study, we rationally designed and synthesized DFX117(6-(5-(2,4-difluorophenylsulfonamido)-6-methoxypyridin-3-yl)-N-(2-morpholinoethyl) imidazo[1,2-a]pyridine-3-carboxamide) as a novel PI3Kα selective inhibitor. Herein, the antitumor activity and underlying mechanisms of DFX117 against non-small cell lung cancer (NSCLC) cells were evaluated in both in vitro and in vivo animal models. Concurrent targeted c-Met and PI3Kα by DFX117 dose-dependent inhibited the cell growth of H1975 cells (PIK3CA mutation and c-Met amplification) and A549 cells (KRAS mutation). DFX117 subsequently induced G0/G1 cell cycle arrest and apoptosis. These data highlight the significant potential of DFX117 as a feasible and efficacious agent for the treatment of NSCLC patients. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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17 pages, 6292 KiB  
Article
Epsilon-Globin HBE1 Enhances Radiotherapy Resistance by Down-Regulating BCL11A in Colorectal Cancer Cells
by Sang Yoon Park, Seon-Jin Lee, Hee Jun Cho, Jong-Tae Kim, Hyang Ran Yoon, Kyung Ho Lee, Bo Yeon Kim, Younghee Lee and Hee Gu Lee
Cancers 2019, 11(4), 498; https://doi.org/10.3390/cancers11040498 - 8 Apr 2019
Cited by 15 | Viewed by 4281
Abstract
Resistance to radiotherapy is considered an important obstacle in the treatment of colorectal cancer. However, the mechanisms that enable tumor cells to tolerate the effects of radiation remain unclear. Moreover, radiotherapy causes accumulated mutations in transcription factors, which can lead to changes in [...] Read more.
Resistance to radiotherapy is considered an important obstacle in the treatment of colorectal cancer. However, the mechanisms that enable tumor cells to tolerate the effects of radiation remain unclear. Moreover, radiotherapy causes accumulated mutations in transcription factors, which can lead to changes in gene expression and radiosensitivity. This phenomenon reduces the effectiveness of radiation therapy towards cancer cells. In the present study, radiation-resistant (RR) cancer cells were established by sequential radiation exposure, and hemoglobin subunit epsilon 1 (HBE1) was identified as a candidate radiation resistance-associated protein based on RNA-sequencing analysis. Then, compared to radiosensitive (RS) cell lines, the overexpression of HBE1 in RR cell lines was used to measure various forms of radiation-induced cellular damage. Consequently, HBE1-overexpressing cell lines were found to exhibit decreased radiation-induced intracellular reactive oxygen species (ROS) production and cell mortality. Conversely, HBE1 deficiency in RR cell lines increased intracellular ROS production, G2/M arrest, and apoptosis, and decreased clonogenic survival rate. These effects were reversed by the ROS scavenger N-acetyl cysteine. Moreover, HBE1 overexpression was found to attenuate radiation-induced endoplasmic reticulum stress and apoptosis via an inositol-requiring enzyme 1(IRE1)—Jun amino-terminal kinase (JNK) signaling pathway. In addition, increased HBE1 expression induced by γ-irradiation in RS cells attenuated expression of the transcriptional regulator BCL11A, whereas its depletion in RR cells increased BCL11A expression. Collectively, these observations indicate that the expression of HBE1 during radiotherapy might potentiate the survival of radiation-exposed colorectal cancer cells. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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16 pages, 4624 KiB  
Article
Heterogeneous Nuclear Ribonucleoproteins A1 and A2 Function in Telomerase-Dependent Maintenance of Telomeres
by Tong-Hong Wang, Chin-Chuan Chen, Yuan-Chao Hsiao, Yu-Han Lin, Wen-Chieh Pi, Pei-Rong Huang, Tzu-Chien V. Wang and Chi-Yuan Chen
Cancers 2019, 11(3), 334; https://doi.org/10.3390/cancers11030334 - 8 Mar 2019
Cited by 13 | Viewed by 3380
Abstract
The A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs A/B), which includes hnRNP A1, A2/B1, and A3, plays an important role in cell proliferation. The simultaneous suppression of hnRNP A1/A2, but not the suppression of hnRNP A1 or A2 alone, has been shown to [...] Read more.
The A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs A/B), which includes hnRNP A1, A2/B1, and A3, plays an important role in cell proliferation. The simultaneous suppression of hnRNP A1/A2, but not the suppression of hnRNP A1 or A2 alone, has been shown to inhibit cell proliferation and induce apoptosis in cancer cells, but not in mortal normal cells. However, the molecular basis for such a differential inhibition of cell proliferation remains unknown. Here, we show that the simultaneous suppression of hnRNP A1 and hnRNP A2 resulted in dysfunctional telomeres and induced DNA damage responses in cancer cells. The inhibition of apoptosis did not alleviate the inhibition of cell proliferation nor the formation of dysfunctional telomeres in cancer cells depleted of hnRNP A1/A2. Moreover, while proliferation of mortal normal fibroblasts was not sensitive to the depletion of hnRNP A1/A2, the ectopic expression of hTERT in normal fibroblasts rendered these cells sensitive to proliferation inhibition, which was associated with the production of dysfunctional telomeres. Our study demonstrates that hnRNP A1 and A2 function to maintain telomeres in telomerase-expressing cells only, suggesting that the maintenance of functional telomeres in telomerase-expressing cancer cells employs factors that differ from those used in the telomerase-negative normal cells. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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25 pages, 42139 KiB  
Article
The Novel Mnk1/2 Degrader and Apoptosis Inducer VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis
by Senthilmurugan Ramalingam, Vidya P. Ramamurthy, Lalji K. Gediya, Francis N. Murigi, Puranik Purushottamachar, Weiliang Huang, Eun Yong Choi, Yuji Zhang, Tadas S Vasaitis, Maureen A. Kane, Rena G. Lapidus and Vincent C. O. Njar
Cancers 2019, 11(3), 299; https://doi.org/10.3390/cancers11030299 - 3 Mar 2019
Cited by 20 | Viewed by 7763
Abstract
Currently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, [...] Read more.
Currently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. Herein, we undertook a comprehensive study to evaluate the activity of a first-in-class Mnk1/2 protein degraders, racemic VNLG-152R and its two enantiomers (VNLG-152E1 and VNLG-152E2) in in vitro and in vivo models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader, superior to its pure enantiomers. By targeting Mnk1/2 protein degradation (activity), VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulated downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable antitumor (91 to 100% growth inhibition) and antimetastatic (~80% inhibition) activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for the effective treatment of patients with primary/metastatic TNBC. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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14 pages, 2391 KiB  
Article
Casticin-Induced Inhibition of Cell Growth and Survival Are Mediated through the Dual Modulation of Akt/mTOR Signaling Cascade
by Jong Hyun Lee, Chulwon Kim, Jae-Young Um, Gautam Sethi and Kwang Seok Ahn
Cancers 2019, 11(2), 254; https://doi.org/10.3390/cancers11020254 - 22 Feb 2019
Cited by 47 | Viewed by 3960
Abstract
The Akt/mTOR signaling cascade is a critical pathway involved in various physiological and pathological conditions, including regulation of cell proliferation, survival, invasion, and angiogenesis. In the present study, we investigated the anti-neoplastic effects of casticin (CTC), identified from the plant Vitex rotundifolia L., [...] Read more.
The Akt/mTOR signaling cascade is a critical pathway involved in various physiological and pathological conditions, including regulation of cell proliferation, survival, invasion, and angiogenesis. In the present study, we investigated the anti-neoplastic effects of casticin (CTC), identified from the plant Vitex rotundifolia L., alone and/or in combination with BEZ-235, a dual Akt/mTOR inhibitor in human tumor cells. We found that CTC exerted a significant dose-dependent cytotoxicity and reduced cell proliferation in a variety of human tumor cells. Also, CTC effectively blocked the phosphorylation levels of Akt (Ser473) and mTOR (Ser2448) proteins as well as induced substantial apoptosis. Additionally treatment with CTC and BEZ-235 in conjunction resulted in a greater apoptotic effect than caused by either agent alone thus implicating the anti-neoplastic effects of this novel combination. Overall, the findings suggest that CTC can interfere with Akt/mTOR signaling cascade involved in tumorigenesis and can be used together with pharmacological agents targeting Akt/mTOR pathway. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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24 pages, 7454 KiB  
Article
A H2AX–CARP-1 Interaction Regulates Apoptosis Signaling Following DNA Damage
by Sreeja C. Sekhar, Jaganathan Venkatesh, Vino T. Cheriyan, Magesh Muthu, Edi Levi, Hadeel Assad, Paul Meister, Vishnu V. Undyala, James W. Gauld and Arun K. Rishi
Cancers 2019, 11(2), 221; https://doi.org/10.3390/cancers11020221 - 14 Feb 2019
Cited by 8 | Viewed by 4091
Abstract
Cell Cycle and Apoptosis Regulatory Protein (CARP-1/CCAR1) is a peri-nuclear phosphoprotein that regulates apoptosis via chemotherapeutic Adriamycin (doxorubicin) and a novel class of CARP-1 functional mimetic (CFM) compounds. Although Adriamycin causes DNA damage, data from Comet assays revealed that CFM-4.16 also induced DNA [...] Read more.
Cell Cycle and Apoptosis Regulatory Protein (CARP-1/CCAR1) is a peri-nuclear phosphoprotein that regulates apoptosis via chemotherapeutic Adriamycin (doxorubicin) and a novel class of CARP-1 functional mimetic (CFM) compounds. Although Adriamycin causes DNA damage, data from Comet assays revealed that CFM-4.16 also induced DNA damage. Phosphorylation of histone 2AX (γH2AX) protein is involved in regulating DNA damage repair and apoptosis signaling. Adriamycin or CFM-4.16 treatments inhibited cell growth and caused elevated CARP-1 and γH2AX in human breast (HBC) and cervical cancer (HeLa) cells. In fact, a robust nuclear or peri-nuclear co-localization of CARP-1 and γH2AX occurred in cells undergoing apoptosis. Knock-down of CARP-1 diminished γH2AX, their co-localization, and apoptosis in CFM-4.16- or Adriamycin-treated cells. We found that CARP-1 directly binds with H2AX, and H2AX interacted with CARP-1, but not CARP-1 (Δ600–652) mutant. Moreover, cells expressing CARP-1 (Δ600–652) mutant were resistant to apoptosis, and had diminished levels of γH2AX, when compared with cells expressing wild-type CARP-1. Mutagenesis studies revealed that H2AX residues 1–35 harbored a CARP-1-binding epitope, while CARP-1 amino acids 636–650 contained an H2AX-interacting epitope. Surface plasmon resonance studies revealed that CARP-1 (636–650) peptide bound with H2AX (1–35) peptide with a dissociation constant (Kd) of 127 nM. Cells expressing enhanced GFP (EGFP)-tagged H2AX (1–35) peptide or EGFP-tagged CARP-1 (636–650) peptide were resistant to inhibition by Adriamycin or CFM-4.16. Treatment of cells with transactivator of transcription (TAT)-tagged CARP-1 (636–650) peptide resulted in a moderate, statistically significant abrogation of Adriamycin-induced growth inhibition of cancer cells. Our studies provide evidence for requirement of CARP-1 interaction with H2AX in apoptosis signaling by Adriamycin and CFM compounds. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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Review

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29 pages, 801 KiB  
Review
Targeting Mitochondrial Apoptosis to Overcome Treatment Resistance in Cancer
by Natalie Yan Li Ngoi, Clarice Choong, Joanne Lee, Gregory Bellot, Andrea LA Wong, Boon Cher Goh and Shazib Pervaiz
Cancers 2020, 12(3), 574; https://doi.org/10.3390/cancers12030574 - 2 Mar 2020
Cited by 45 | Viewed by 7593
Abstract
Deregulated cellular apoptosis is a hallmark of cancer and chemotherapy resistance. The B-cell lymphoma 2 (BCL-2) protein family members are sentinel molecules that regulate the mitochondrial apoptosis machinery and arbitrate cell fate through a delicate balance between pro- and anti-apoptotic factors. The recognition [...] Read more.
Deregulated cellular apoptosis is a hallmark of cancer and chemotherapy resistance. The B-cell lymphoma 2 (BCL-2) protein family members are sentinel molecules that regulate the mitochondrial apoptosis machinery and arbitrate cell fate through a delicate balance between pro- and anti-apoptotic factors. The recognition of the anti-apoptotic BCL2 gene as an oncogenic driver in hematological malignancies has directed attention toward unraveling the biological significance of each of the BCL-2 superfamily members in cancer progression and garnered interest in the targeting of apoptosis in cancer therapy. Accordingly, the approval of venetoclax (ABT-199), a small molecule BCL-2 inhibitor, in patients with chronic lymphocytic leukemia and acute myeloid leukemia has become the proverbial torchbearer for novel candidate drug approaches selectively targeting the BCL-2 superfamily. Despite the inspiring advances in this field, much remains to be learned regarding the optimal therapeutic context for BCL-2 targeting. Functional assays, such as through BH3 profiling, may facilitate prediction of treatment response, development of drug resistance and shed light on rational combinations of BCL-2 inhibitors with other branches of cancer therapy. This review summarizes the pathological roles of the BCL-2 family members in cancer, discusses the current landscape of their targeting in clinical practice, and highlights the potential for future therapeutic inroads in this important area. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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20 pages, 2672 KiB  
Review
Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer
by Priya D. Gopal Krishnan, Emily Golden, Eleanor A. Woodward, Nathan J. Pavlos and Pilar Blancafort
Cancers 2020, 12(2), 259; https://doi.org/10.3390/cancers12020259 - 21 Jan 2020
Cited by 42 | Viewed by 6066
Abstract
The Rab GTPase family of proteins are mediators of membrane trafficking, conferring identity to the cell membranes. Recently, Rab and Rab-associated factors have been recognized as major regulators of the intracellular positioning and activity of signaling pathways regulating cell growth, survival and programmed [...] Read more.
The Rab GTPase family of proteins are mediators of membrane trafficking, conferring identity to the cell membranes. Recently, Rab and Rab-associated factors have been recognized as major regulators of the intracellular positioning and activity of signaling pathways regulating cell growth, survival and programmed cell death or apoptosis. Membrane trafficking mediated by Rab proteins is controlled by intracellular localization of Rab proteins, Rab-membrane interactions and GTP-activation processes. Aberrant expression of Rab proteins has been reported in multiple cancers such as lung, brain and breast malignancies. Mutations in Rab-coding genes and/or post-translational modifications in their protein products disrupt the cellular vesicle trafficking network modulating tumorigenic potential, cellular migration and metastatic behavior. Conversely, Rabs also act as tumor suppressive factors inducing apoptosis and inhibiting angiogenesis. Deconstructing the signaling mechanisms modulated by Rab proteins during apoptosis could unveil underlying molecular mechanisms that may be exploited therapeutically to selectively target malignant cells. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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25 pages, 2340 KiB  
Review
Therapeutic Inducers of Apoptosis in Ovarian Cancer
by Mudra Binju, Monica Angelica Amaya-Padilla, Graeme Wan, Hendra Gunosewoyo, Yohan Suryo Rahmanto and Yu Yu
Cancers 2019, 11(11), 1786; https://doi.org/10.3390/cancers11111786 - 13 Nov 2019
Cited by 49 | Viewed by 6641
Abstract
Ovarian cancers remain one of the most common causes of gynecologic cancer-related death in women worldwide. The standard treatment comprises platinum-based chemotherapy, and most tumors develop resistance to therapeutic drugs. One mechanism of developing drug resistance is alterations of molecules involved in apoptosis, [...] Read more.
Ovarian cancers remain one of the most common causes of gynecologic cancer-related death in women worldwide. The standard treatment comprises platinum-based chemotherapy, and most tumors develop resistance to therapeutic drugs. One mechanism of developing drug resistance is alterations of molecules involved in apoptosis, ultimately assisting in the cells’ capability to evade death. Thus, there is a need to focus on identifying potential drugs that restore apoptosis in cancer cells. Here, we discuss the major inducers of apoptosis mediated through various mechanisms and their usefulness as potential future treatment options for ovarian cancer. Broadly, they can target the apoptotic pathways directly or affect apoptosis indirectly through major cancer-pathways in cells. The direct apoptotic targets include the Bcl-2 family of proteins and the inhibitor of apoptotic proteins (IAPs). However, indirect targets include processes related to homologous recombination DNA repair, micro-RNA, and p53 mutation. Besides, apoptosis inducers may also disturb major pathways converging into apoptotic signals including janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), wingless-related integration site (Wnt)/β-Catenin, mesenchymal-epithelial transition factor (MET)/hepatocyte growth factor (HGF), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)/v-AKT murine thymoma viral oncogene homologue (AKT)/mammalian target of rapamycin (mTOR) pathways. Several drugs in our review are undergoing clinical trials, for example, birinapant, DEBIO-1143, Alisertib, and other small molecules are in preclinical investigations showing promising results in combination with chemotherapy. Molecules that exhibit better efficacy in the treatment of chemo-resistant cancer cells are of interest but require more extensive preclinical and clinical evaluation. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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27 pages, 2525 KiB  
Review
Understanding and Targeting Apoptotic Pathways in Ovarian Cancer
by Linah F. Al-Alem, Andrew T. Baker, Unnati M. Pandya, Eric L. Eisenhauer and Bo R. Rueda
Cancers 2019, 11(11), 1631; https://doi.org/10.3390/cancers11111631 - 24 Oct 2019
Cited by 22 | Viewed by 6107
Abstract
Ovarian cancer cells evade the immune system as well as chemotherapeutic and/or biologic treatments through inherent or acquired mechanisms of survival and drug resistance. Depending on the cell type and the stimuli, this threshold can range from external forces such as blunt trauma [...] Read more.
Ovarian cancer cells evade the immune system as well as chemotherapeutic and/or biologic treatments through inherent or acquired mechanisms of survival and drug resistance. Depending on the cell type and the stimuli, this threshold can range from external forces such as blunt trauma to programmed processes such as apoptosis, autophagy, or necroptosis. This review focuses on apoptosis, which is one form of programmed cell death. It highlights the multiple signaling pathways that promote or inhibit apoptosis and reviews current clinical therapies that target apoptotic pathways in ovarian cancer. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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21 pages, 3402 KiB  
Review
Destined to Die: Apoptosis and Pediatric Cancers
by Zhang’e Choo, Amos Hong Pheng Loh and Zhi Xiong Chen
Cancers 2019, 11(11), 1623; https://doi.org/10.3390/cancers11111623 - 23 Oct 2019
Cited by 14 | Viewed by 4014
Abstract
Apoptosis (programmed cell death) is a systematic and coordinated cellular process that occurs in physiological and pathophysiological conditions. Sidestepping or resisting apoptosis is a distinct characteristic of human cancers including childhood malignancies. This review dissects the apoptosis pathways implicated in pediatric tumors. Understanding [...] Read more.
Apoptosis (programmed cell death) is a systematic and coordinated cellular process that occurs in physiological and pathophysiological conditions. Sidestepping or resisting apoptosis is a distinct characteristic of human cancers including childhood malignancies. This review dissects the apoptosis pathways implicated in pediatric tumors. Understanding these pathways not only unraveled key molecules that may serve as potential targets for drug discovery, but also molecular nodes that integrate with other signaling networks involved in processes such as development. This review presents current knowledge of the complex regulatory system that governs apoptosis with respect to other processes in pediatric cancers, so that fresh insights may be derived regarding treatment resistance or for more effective treatment options. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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24 pages, 1088 KiB  
Review
Bioactive Compounds: Multi-Targeting Silver Bullets for Preventing and Treating Breast Cancer
by Nethaji Muniraj, Sumit Siddharth and Dipali Sharma
Cancers 2019, 11(10), 1563; https://doi.org/10.3390/cancers11101563 - 15 Oct 2019
Cited by 29 | Viewed by 6638
Abstract
Each cell in our body is designed with a self-destructive trigger, and if damaged, can happily sacrifice itself for the sake of the body. This process of self-destruction to safeguard the adjacent normal cells is known as programmed cell death or apoptosis. Cancer [...] Read more.
Each cell in our body is designed with a self-destructive trigger, and if damaged, can happily sacrifice itself for the sake of the body. This process of self-destruction to safeguard the adjacent normal cells is known as programmed cell death or apoptosis. Cancer cells outsmart normal cells and evade apoptosis and it is one of the major hallmarks of cancer. The cardinal quest for anti-cancer drug discovery (bioactive or synthetic compounds) is to be able to re-induce the so called “programmed cell death” in cancer cells. The importance of bioactive compounds as the linchpin of cancer therapeutics is well known as many effective chemotherapeutic drugs such as vincristine, vinblastine, doxorubicin, etoposide and paclitaxel have natural product origins. The present review discusses various bioactive compounds with known anticancer potential, underlying mechanisms by which they induce cell death and their preclinical/clinical development. Most bioactive compounds can concurrently target multiple signaling pathways that are important for cancer cell survival while sparing normal cells hence they can potentially be the silver bullets for targeting cancer growth and metastatic progression. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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24 pages, 3117 KiB  
Review
Autophagy Function and Dysfunction: Potential Drugs as Anti-Cancer Therapy
by Francesca Cuomo, Lucia Altucci and Gilda Cobellis
Cancers 2019, 11(10), 1465; https://doi.org/10.3390/cancers11101465 - 29 Sep 2019
Cited by 50 | Viewed by 5271
Abstract
Autophagy is a highly conserved catabolic and energy-generating process that facilitates the degradation of damaged organelles or intracellular components, providing cells with components for the synthesis of new ones. Autophagy acts as a quality control system, and has a pro-survival role. The imbalance [...] Read more.
Autophagy is a highly conserved catabolic and energy-generating process that facilitates the degradation of damaged organelles or intracellular components, providing cells with components for the synthesis of new ones. Autophagy acts as a quality control system, and has a pro-survival role. The imbalance of this process is associated with apoptosis, which is a “positive” and desired biological choice in some circumstances. Autophagy dysfunction is associated with several diseases, including neurodegenerative disorders, cardiomyopathy, diabetes, liver disease, autoimmune diseases, and cancer. Here, we provide an overview of the regulatory mechanisms underlying autophagy, with a particular focus on cancer and the autophagy-targeting drugs currently approved for use in the treatment of solid and non-solid malignancies. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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27 pages, 3665 KiB  
Review
Purine-Metabolising Enzymes and Apoptosis in Cancer
by Marcella Camici, Mercedes Garcia-Gil, Rossana Pesi, Simone Allegrini and Maria Grazia Tozzi
Cancers 2019, 11(9), 1354; https://doi.org/10.3390/cancers11091354 - 12 Sep 2019
Cited by 54 | Viewed by 7251
Abstract
The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in [...] Read more.
The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in dividing and tumour cells that require a greater amount of nucleotides. An imbalance in the purine pools is fundamental not only for preventing cell proliferation, but also, in many cases, to promote apoptosis. It is known that tumour cells harbour several mutations that might lead to defective apoptosis-inducing pathways, and this is probably at the basis of the initial expansion of the population of neoplastic cells. Therefore, knowledge of the molecular mechanisms that lead to apoptosis of tumoural cells is key to predicting the possible success of a drug treatment and planning more effective and focused therapies. In this review, we describe how the modulation of enzymes involved in purine metabolism in tumour cells may affect the apoptotic programme. The enzymes discussed are: ectosolic and cytosolic 5′-nucleotidases, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyltransferase, and inosine-5′-monophosphate dehydrogenase, as well as recently described enzymes particularly expressed in tumour cells, such as deoxynucleoside triphosphate triphosphohydrolase and 7,8-dihydro-8-oxoguanine triphosphatase. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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Graphical abstract

13 pages, 761 KiB  
Review
ADRB2-Targeting Therapies for Prostate Cancer
by George Kulik
Cancers 2019, 11(3), 358; https://doi.org/10.3390/cancers11030358 - 13 Mar 2019
Cited by 27 | Viewed by 4850
Abstract
There is accumulating evidence that β-2 adrenergic receptor (ADRB2) signaling contributes to the progression and therapy resistance of prostate cancer, whereas availability of clinically tested β-blocker propranolol makes this pathway especially attractive as potential therapeutic target. Yet even in tumors with active ADRB2 [...] Read more.
There is accumulating evidence that β-2 adrenergic receptor (ADRB2) signaling contributes to the progression and therapy resistance of prostate cancer, whereas availability of clinically tested β-blocker propranolol makes this pathway especially attractive as potential therapeutic target. Yet even in tumors with active ADRB2 signaling propranolol may be ineffective. Inhibition of apoptosis is one of the major mechanisms by which activation of ADRB2 contributes to prostate cancer pathophysiology. The signaling network that controls apoptosis in prostate tumors is highly redundant, with several signaling pathways targeting a few critical apoptosis regulatory molecules. Therefore, a comprehensive analysis of ADRB2 signaling in the context of other signaling mechanisms is necessary to identify patients who will benefit from propranolol therapy. This review discusses how information on the antiapoptotic mechanisms activated by ADRB2 can guide clinical trials of ADRB2 antagonist propranolol as potential life-extending therapy for prostate cancer. To select patients for clinical trials of propranolol three classes of biomarkers are proposed. First, biomarkers of ADRB2/cAMP-dependent protein kinase (PKA) pathway activation; second, biomarkers that inform about activation of other signaling pathways unrelated to ADRB2; third, apoptosis regulatory molecules controlled by ADRB2 signaling and other survival signaling pathways. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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20 pages, 2041 KiB  
Review
Chemotherapy Resistance Explained through Endoplasmic Reticulum Stress-Dependent Signaling
by Entaz Bahar, Ji-Ye Kim and Hyonok Yoon
Cancers 2019, 11(3), 338; https://doi.org/10.3390/cancers11030338 - 8 Mar 2019
Cited by 67 | Viewed by 10263
Abstract
Cancers cells have the ability to develop chemotherapy resistance, which is a persistent problem during cancer treatment. Chemotherapy resistance develops through different molecular mechanisms, which lead to modification of the cancer cells signals needed for cellular proliferation or for stimulating an immune response. [...] Read more.
Cancers cells have the ability to develop chemotherapy resistance, which is a persistent problem during cancer treatment. Chemotherapy resistance develops through different molecular mechanisms, which lead to modification of the cancer cells signals needed for cellular proliferation or for stimulating an immune response. The endoplasmic reticulum (ER) is an important organelle involved in protein quality control, by promoting the correct folding of protein and ER-mediated degradation of unfolded or misfolded protein, namely, ER-associated degradation. Disturbances of the normal ER functions causes an accumulation of unfolded or misfolded proteins in the ER lumen, resulting in a condition called “ER stress (ERS).” ERS triggers the unfolded protein response (UPR)—also called the ERS response (ERSR)—to restore homeostasis or activate cell death. Although the ERSR is one emerging potential target for chemotherapeutics to treat cancer, it is also critical for chemotherapeutics resistance, as well. However, the detailed molecular mechanism of the relationship between the ERSR and tumor survival or drug resistance remains to be fully understood. In this review, we aim to describe the most vital molecular mechanism of the relationship between the ERSR and chemotherapy resistance. Moreover, the review also discusses the molecular mechanism of ER stress-mediated apoptosis on cancer treatments. Full article
(This article belongs to the Special Issue Apoptosis in Cancer)
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