Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.8
5.6
Journals
IJMS
Special Issues
Cell Apoptosis
ijms-logo
Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

► Journal Menu

Journal Browser

► Journal Browser
share announcement

Cell Apoptosis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 54391

Special Issue Editor

Prof. Dr. Francisco Estevez

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, University Institute for Biomedical and Healthcare Research (IUIBS), University of Las Palmas de Gran Canaria, 35016 Las Palmas de Gran Canaria, Spain
Interests: apoptosis; caspase; cell cycle; cell proliferation; cytotoxicity; in vitro antiproliferative activity; mitogen-activated protein kinases; reactive oxygen species; structure–activity relationship
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Apoptosis is a form of regulated cell death that plays a major role in an array of physiological and pathophysiological conditions. The execution of apoptosis is triggered by distinct and interconnected signaling pathways. Together with sustained proliferative signaling, the resistance to apoptosis is recognized as one of the cellular hallmarks of cancer. Exponential progress in our understanding of the regulation of death and survival signaling cascades has recently been achieved. This includes the executioners of apoptosis, B-cell lymphoma 2 family proteins, and oxidative stress. New advances in this field will allow for the identification of new modulators of the pathways in cell death and survival. This knowledge may contribute to the preparation of therapeutic strategies of interest in medicine. It includes the ability to potentiate the cytotoxicity against malignant cells and has potential application in other metabolic or immunological diseases. This Special Issue aims to improve our understanding of the molecular mechanisms involved in apoptosis. Contributions may relate to the events triggered by different physical and chemical agents, including naturally occurring and synthetic compounds, and/or by physiological and pathophysiological conditions.

Dr. Francisco Estevez
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • caspase
  • cell cycle
  • cytotoxicity
  • reactive oxygen species.

Published Papers (21 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

15 pages, 8233 KiB  
Article
DHA Induces Cell Death through the Production of ROS and the Upregulation of CHOP in Fibroblast-like Synovial Cells from Human Rheumatoid Arthritis Patients
by Mini Jeong, Jong-Il Shin, Jaewook Cho, Yong-Joon Jeon, Jin-Hyun Kim, Jeehee Youn and Kyungho Lee
Int. J. Mol. Sci. 2023, 24(2), 1734; https://doi.org/10.3390/ijms24021734 - 15 Jan 2023
Viewed by 1588
Abstract
Rheumatoid arthritis (RA) is an inflammatory disease marked by a massive proliferation of synovial cells in the joints. In this study, we investigated the pro-apoptotic effects of docosahexaenoic acid (DHA) in human fibroblast-like synovial cells from RA patients (RA-FLS). An in vitro study [...] Read more.
Rheumatoid arthritis (RA) is an inflammatory disease marked by a massive proliferation of synovial cells in the joints. In this study, we investigated the pro-apoptotic effects of docosahexaenoic acid (DHA) in human fibroblast-like synovial cells from RA patients (RA-FLS). An in vitro study using MH7A cells showed that DHA treatment induced caspase-8-dependent apoptosis in a dose-dependent manner and reduced the TNF-α-mediated induction of MMP-9 and IL-1β. DHA also induced the phosphorylation of eIF2α, the expression of the ER stress markers ATF4 and C/EBP homologous protein (CHOP), and death receptor 5 (DR5). The knockdown of CHOP or DR5 increased cell viability and reduced apoptosis in DHA-treated cells. Furthermore, the knockdown of CHOP reduced DHA-mediated DR5 expression, while the overexpression of CHOP increased DR5 expression. We also found that DHA treatment induced the accumulation of reactive oxygen species (ROS), and pretreatment with the anti-oxidant Tiron effectively abrogated not only the expression of CHOP and DR5, but also DHA-induced apoptosis. Under this condition, cell viability was increased, while PARP-1 cleavage and caspase-8 activation were reduced. All the findings were reproduced in human primary synovial cells obtained from RA patients. These results suggest that the DHA-mediated induction of ROS and CHOP induced apoptosis through the upregulation of DR5 in RA-FLSs, and that CHOP could be used as a therapy for RA. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

25 pages, 7699 KiB  
Article
Chalcone-Acridine Hybrid Suppresses Melanoma Cell Progression via G2/M Cell Cycle Arrest, DNA Damage, Apoptosis, and Modulation of MAP Kinases Activity
by Maria Gazdova, Radka Michalkova, Martin Kello, Maria Vilkova, Zuzana Kudlickova, Janette Baloghova, Ladislav Mirossay and Jan Mojzis
Int. J. Mol. Sci. 2022, 23(20), 12266; https://doi.org/10.3390/ijms232012266 - 14 Oct 2022
Cited by 3 | Viewed by 1637
Abstract
This study was focused on investigating the antiproliferative effects of chalcone hybrids in melanoma cancer cells. Among seven chalcone hybrids, the chalcone-acridine hybrid 1C was the most potent and was selected for further antiproliferative mechanism studies. This in vitro study revealed the potent [...] Read more.
This study was focused on investigating the antiproliferative effects of chalcone hybrids in melanoma cancer cells. Among seven chalcone hybrids, the chalcone-acridine hybrid 1C was the most potent and was selected for further antiproliferative mechanism studies. This in vitro study revealed the potent antiproliferative effect of 1C via cell cycle arrest and apoptosis induction. Cell cycle arrest at the G2/M phase was associated with modulation of expression or phosphorylation of specific cell cycle-associated proteins (cyclin B1, p21, and ChK1), tubulins, as well as with the activation of the DNA damage response pathway. Chalcone 1C also induced apoptosis accompanied by mitochondrial dysfunction evidenced by a decrease in mitochondrial membrane potential, increase in Bax/Bcl-xL ratio and cytochrome c release followed by caspase 3/7 activation. In addition, increased phosphorylation of MAP kinases (Erk1/2, p38 and JNK) was observed in chalcone 1C-treated melanoma cells. The strong antiproliferative activities of this chalcone-acridine hybrid suggest that it may be useful as an antimelanoma agent in humans. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

29 pages, 3918 KiB  
Article
GSK3β Inhibition Is the Molecular Pivot That Underlies the Mir-210-Induced Attenuation of Intrinsic Apoptosis Cascade during Hypoxia
by Gurdeep Marwarha, Øystein Røsand, Katrine Hordnes Slagsvold and Morten Andre Høydal
Int. J. Mol. Sci. 2022, 23(16), 9375; https://doi.org/10.3390/ijms23169375 - 19 Aug 2022
Cited by 2 | Viewed by 1438
Abstract
Apoptotic cell death is a deleterious consequence of hypoxia-induced cellular stress. The master hypoxamiR, microRNA-210 (miR-210), is considered the primary driver of the cellular response to hypoxia stress. We have recently demonstrated that miR-210 attenuates hypoxia-induced apoptotic cell death. In this paper, [...] Read more.
Apoptotic cell death is a deleterious consequence of hypoxia-induced cellular stress. The master hypoxamiR, microRNA-210 (miR-210), is considered the primary driver of the cellular response to hypoxia stress. We have recently demonstrated that miR-210 attenuates hypoxia-induced apoptotic cell death. In this paper, we unveil that the miR-210-induced inhibition of the serine/threonine kinase Glycogen Synthase Kinase 3 beta (GSK3β) in AC-16 cardiomyocytes subjected to hypoxia stress underlies the salutary protective response of miR-210 in mitigating the hypoxia-induced apoptotic cell death. Using transient overexpression vectors to augment miR-210 expression concomitant with the ectopic expression of the constitutive active GSK3β S9A mutant (ca-GSK3β S9A), we exhaustively performed biochemical and molecular assays to determine the status of the hypoxia-induced intrinsic apoptosis cascade. Caspase-3 activity analysis coupled with DNA fragmentation assays cogently demonstrate that the inhibition of GSK3β kinase activity underlies the miR-210-induced attenuation in the hypoxia-driven apoptotic cell death. Further elucidation and delineation of the upstream cellular events unveiled an indispensable role of the inhibition of GSK3β kinase activity in mediating the miR-210-induced mitigation of the hypoxia-driven BAX and BAK insertion into the outer mitochondria membrane (OMM) and the ensuing Cytochrome C release into the cytosol. Our study is the first to unveil that the inhibition of GSK3β kinase activity is indispensable in mediating the miR-210-orchestrated protective cellular response to hypoxia-induced apoptotic cell death. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

21 pages, 5166 KiB  
Article
Emodin Sensitizes Cervical Cancer Cells to Vinblastine by Inducing Apoptosis and Mitotic Death
by Wojciech Trybus, Ewa Trybus and Teodora Król
Int. J. Mol. Sci. 2022, 23(15), 8510; https://doi.org/10.3390/ijms23158510 - 31 Jul 2022
Cited by 3 | Viewed by 2026
Abstract
In recent years, studies on the effects of combining novel plant compounds with cytostatics used in cancer therapy have received considerable attention. Since emodin sensitizes tumor cells to chemotherapeutics, we evaluated changes in cervical cancer cells after its combination with the antimitotic drug [...] Read more.
In recent years, studies on the effects of combining novel plant compounds with cytostatics used in cancer therapy have received considerable attention. Since emodin sensitizes tumor cells to chemotherapeutics, we evaluated changes in cervical cancer cells after its combination with the antimitotic drug vinblastine. Cellular changes were demonstrated using optical, fluorescence, confocal and electron microscopy. Cell viability was assessed by MTT assay. The level of apoptosis, caspase 3/7, Bcl-2 protein, ROS, mitochondrial membrane depolarization, cell cycle and degree of DNA damage were analyzed by flow cytometry. The microscopic image showed indicators characteristic for emodin- and vinblastine-induced mitotic catastrophe, i.e., multinucleated cells, giant cells, cells with micronuclei, and abnormal mitotic figures. These compounds also increased blocking of cells in the G2/M phase, and the generated ROS induced swelling and mitochondrial damage. This translated into the growth of apoptotic cells with active caspase 3/7 and inactivation of Bcl-2 protein and active ATM kinase. Emodin potentiated the cytotoxic effect of vinblastine, increasing oxidative stress, mitotic catastrophe and apoptosis. Preliminary studies show that the combined action of both compounds, may constitute an interesting form of anticancer therapy. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

15 pages, 7211 KiB  
Article
Ciliary Neurotrophic Factor (CNTF) and Its Receptors Signal Regulate Cementoblasts Apoptosis through a Mechanism of ERK1/2 and Caspases Signaling
by Jiawen Yong, Sabine Groeger, Julia von Bremen and Sabine Ruf
Int. J. Mol. Sci. 2022, 23(15), 8335; https://doi.org/10.3390/ijms23158335 - 28 Jul 2022
Cited by 5 | Viewed by 1742
Abstract
Ciliary neurotrophic factor (CNTF) was identified as a survival factor in various types of peripheral and central neurons, glia and non-neural cells. At present, there is no available data on the expression and localization of CNTF-receptors in cementoblasts as well as on the [...] Read more.
Ciliary neurotrophic factor (CNTF) was identified as a survival factor in various types of peripheral and central neurons, glia and non-neural cells. At present, there is no available data on the expression and localization of CNTF-receptors in cementoblasts as well as on the role of exogenous CNTF on this cell line. The purpose of this study was to determine if cementoblasts express CNTF-receptors and analyze the mechanism of its apoptotic regulation effects on cementoblasts. OCCM-30 cementoblasts were cultivated and stimulated kinetically using CNTF protein (NBP2-35168, Novus Biologicals). Quantified transcriptional (RT-qPCR) and translational (WB) products of CNTFRα, IL-6Rα (CD126), LIFR, p-GP130, GP130, p-ERK1/2, ERK1/2, Caspase-8, -9, -3 and cleaved-caspase-3 were evaluated. Immunofluorescence (IF) staining was applied to visualize the localization of the CNTF-receptors within cells. The apoptosis ratio was measured with an Annexin-V FITC/PI kit. The ERK1/2 antagonist (FR180204, Calbiochem) was added for further investigation by flow cytometry analysis. The CNTF-receptor complex (CNTFRα, LIFR, GP130) was functionally up-regulated in cementoblasts while cultivated with exogenous CNTF. CNTF significantly attenuated cell viability and proliferation for long-term stimulation. Flow cytometry analysis shows that CNTF enhanced the apoptosis after prolonged duration. However, after only a short-term period, CNTF halts the apoptosis of cementoblasts. Further studies revealed that CNTF activated phosphorylated GP130 and the anti-apoptotic molecule ERK1/2 signaling to participate in the regulation of the apoptosis ratio of cementoblasts. In conclusion, CNTF elicited the cellular functions through a notable induction of its receptor complex in cementoblasts. CNTF has an inhibitory effect on the cementoblast homeostasis. These data also elucidate a cellular mechanism for an exogenous CNTF-triggered apoptosis regulation in a mechanism of ERK1/2 and caspase signaling and provides insight into the complex cellular responses induced by CNTF in cementoblasts. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

16 pages, 3907 KiB  
Article
Poly(ADP-ribose) Polymerase 1 Mediates Rab5 Inactivation after DNA Damage
by Masato Mashimo, Akane Morozumi, Akari Nobeyama, Misato Kanzaki, Shigeru Negi, Jiro Kato, Joel Moss, Atsuo Nomura and Takeshi Fujii
Int. J. Mol. Sci. 2022, 23(14), 7827; https://doi.org/10.3390/ijms23147827 - 15 Jul 2022
Cited by 1 | Viewed by 1773
Abstract
Parthanatos is programmed cell death mediated by poly(ADP-ribose) polymerase 1 (PARP1) after DNA damage. PARP1 acts by catalyzing the transfer of poly(ADP-ribose) (PAR) polymers to various nuclear proteins. PAR is subsequently cleaved, generating protein-free PAR polymers, which are translocated to the cytoplasm where [...] Read more.
Parthanatos is programmed cell death mediated by poly(ADP-ribose) polymerase 1 (PARP1) after DNA damage. PARP1 acts by catalyzing the transfer of poly(ADP-ribose) (PAR) polymers to various nuclear proteins. PAR is subsequently cleaved, generating protein-free PAR polymers, which are translocated to the cytoplasm where they associate with cytoplasmic and mitochondrial proteins, altering their functions and leading to cell death. Proteomic studies revealed that several proteins involved in endocytosis bind PAR after PARP1 activation, suggesting endocytosis may be affected by the parthanatos process. Endocytosis is a mechanism for cellular uptake of membrane-impermeant nutrients. Rab5, a small G-protein, is associated with the plasma membrane and early endosomes. Once activated by binding GTP, Rab5 recruits its effectors to early endosomes and regulates their fusion. Here, we report that after DNA damage, PARP1-generated PAR binds to Rab5, suppressing its activity. As a result, Rab5 is dissociated from endosomal vesicles, inhibiting the uptake of membrane-impermeant nutrients. This PARP1-dependent inhibition of nutrient uptake leads to cell starvation and death. It thus appears that this mechanism may represent a novel parthanatos pathway. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

14 pages, 3007 KiB  
Article
Group II Metabotropic Glutamate Receptors Reduce Apoptosis and Regulate BDNF and GDNF Levels in Hypoxic-Ischemic Injury in Neonatal Rats
by Ewelina Bratek-Gerej, Apolonia Ziembowicz and Elzbieta Salinska
Int. J. Mol. Sci. 2022, 23(13), 7000; https://doi.org/10.3390/ijms23137000 - 23 Jun 2022
Cited by 8 | Viewed by 1428
Abstract
Birth asphyxia causes brain injury in neonates, but a fully successful treatment has yet to be developed. This study aimed to investigate the effect of group II mGlu receptors activation after experimental birth asphyxia (hypoxia-ischemia) on the expression of factors involved in apoptosis [...] Read more.
Birth asphyxia causes brain injury in neonates, but a fully successful treatment has yet to be developed. This study aimed to investigate the effect of group II mGlu receptors activation after experimental birth asphyxia (hypoxia-ischemia) on the expression of factors involved in apoptosis and neuroprotective neurotrophins. Hypoxia-ischemia (HI) on 7-day-old rats was used as an experimental model. The effects of intraperitoneal application of mGluR2 agonist LY379268 (5 mg/kg) and the specific mGluR3 agonist NAAG (5 mg/kg) (1 h or 6 h after HI) on apoptotic processes and initiation of the neuroprotective mechanism were investigated. LY379268 and NAAG applied shortly after HI prevented brain damage and significantly decreased pro-apoptotic Bax and HtrA2/Omi expression, increasing expression of anti-apoptotic Bcl-2. NAAG or LY379268 applied at both times also decreased HIF-1α formation. HI caused a significant decrease in BDNF concentration, which was restored after LY379268 or NAAG administration. HI-induced increase in GDNF concentration was decreased after administration of LY379268 or NAAG. Our results show that activation of mGluR2/3 receptors shortly after HI prevents brain damage by the inhibition of excessive glutamate release and apoptotic damage decrease. mGluR2 and mGluR3 agonists produced comparable results, indicating that both receptors may be a potential target for early treatment in neonatal HI. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

22 pages, 8971 KiB  
Article
E2F1 Expression and Apoptosis Initiation in Crayfish and Rat Peripheral Neurons and Glial Cells after Axonal Injury
by Valentina Dzreyan, Moez Eid, Stanislav Rodkin, Maria Pitinova and Svetlana Demyanenko
Int. J. Mol. Sci. 2022, 23(8), 4451; https://doi.org/10.3390/ijms23084451 - 18 Apr 2022
Cited by 5 | Viewed by 2266
Abstract
Neurotrauma is among the main causes of human disability and mortality. The transcription factor E2F1 is one of the key proteins that determine the fate of cells. The involvement of E2F1 in the regulation of survival and death of peripheral nerve cells after [...] Read more.
Neurotrauma is among the main causes of human disability and mortality. The transcription factor E2F1 is one of the key proteins that determine the fate of cells. The involvement of E2F1 in the regulation of survival and death of peripheral nerve cells after axotomy has not been previously studied. We, for the first time, studied axotomy-induced changes in the expression and localization of E2F1 following axonal injury in rats and crayfish. Immunoblotting and immunofluorescence microscopy were used for the analysis of the expression and intracellular localization of E2F1 and its changes after axotomy. To evaluate whether this transcription factor promotes cell apoptosis, we examined the effect of pharmacological inhibition of E2F activity in axotomized rat models. In this work, axotomy caused increased expression of E2F1 as early as 4 h and even 1 h after axotomy of mechanoreceptor neurons and ganglia of crayfish ventral nerve cord (VNC), as well as rat dorsal root ganglia (DRG). The level of E2F1 expression increased both in the cytoplasm and the nuclei of neurons. Pharmacological inhibition of E2F demonstrated a pronounced neuroprotective activity against axotomized DRGs. E2F1 and downstream targets could be considered promising molecular targets for the development of potential neuroprotective agents. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Graphical abstract

19 pages, 2168 KiB  
Article
Metazoans and Intrinsic Apoptosis: An Evolutionary Analysis of the Bcl-2 Family
by Chathura D. Suraweera, Suresh Banjara, Mark G. Hinds and Marc Kvansakul
Int. J. Mol. Sci. 2022, 23(7), 3691; https://doi.org/10.3390/ijms23073691 - 28 Mar 2022
Cited by 8 | Viewed by 2462
Abstract
The B-cell lymphoma-2 (Bcl-2) family is a group of genes regulating intrinsic apoptosis, a process controlling events such as development, homeostasis and the innate and adaptive immune responses in metazoans. In higher organisms, Bcl-2 proteins coordinate intrinsic apoptosis through their regulation of the [...] Read more.
The B-cell lymphoma-2 (Bcl-2) family is a group of genes regulating intrinsic apoptosis, a process controlling events such as development, homeostasis and the innate and adaptive immune responses in metazoans. In higher organisms, Bcl-2 proteins coordinate intrinsic apoptosis through their regulation of the integrity of the mitochondrial outer membrane; this function appears to have originated in the basal metazoans. Bcl-2 genes predate the cnidarian-bilaterian split and have been identified in porifera, placozoans and cnidarians but not ctenophores and some nematodes. The Bcl-2 family is composed of two groups of proteins, one with an α-helical Bcl-2 fold that has been identified in porifera, placozoans, cnidarians, and almost all higher bilaterians. The second group of proteins, the BH3-only group, has little sequence conservation and less well-defined structures and is found in cnidarians and most bilaterians, but not porifera or placozoans. Here we examine the evolutionary relationships between Bcl-2 proteins. We show that the structures of the Bcl-2-fold proteins are highly conserved over evolutionary time. Some metazoans such as the urochordate Oikopleura dioica have lost all Bcl-2 family members. This gene loss indicates that Bcl-2 regulated apoptosis is not an absolute requirement in metazoans, a finding mirrored in recent gene deletion studies in mice. Sequence analysis suggests that at least some Bcl-2 proteins lack the ability to bind BH3-only antagonists and therefore potentially have other non-apoptotic functions. By examining the foundations of the Bcl-2 regulated apoptosis, functional relationships may be clarified that allow us to understand the role of specific Bcl-2 proteins in evolution and disease. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

13 pages, 3121 KiB  
Article
Wnt/β-Catenin Signaling Contributes to Paclitaxel Resistance in Bladder Cancer Cells with Cancer Stem Cell-Like Properties
by Rocío Jiménez-Guerrero, Alejandro Belmonte-Fernández, M. Luz Flores, Mónica González-Moreno, Begoña Pérez-Valderrama, Francisco Romero, Miguel Á. Japón and Carmen Sáez
Int. J. Mol. Sci. 2022, 23(1), 450; https://doi.org/10.3390/ijms23010450 - 31 Dec 2021
Cited by 17 | Viewed by 2065
Abstract
The Wnt/β-catenin pathway plays an important role in tumor progression and chemotherapy resistance and seems to be essential for the maintenance of cancer stem cells (CSC) in several tumor types. However, the interplay of these factors has not been fully addressed in bladder [...] Read more.
The Wnt/β-catenin pathway plays an important role in tumor progression and chemotherapy resistance and seems to be essential for the maintenance of cancer stem cells (CSC) in several tumor types. However, the interplay of these factors has not been fully addressed in bladder cancer. Here, our goal was to analyze the role of the Wnt/β-catenin pathway in paclitaxel resistance and to study the therapeutic efficacy of its inhibition in bladder cancer cells, as well as to determine its influence in the maintenance of the CSC-like phenotype in bladder cancer. Our results show that paclitaxel-resistant HT1197 cells have hyperactivation of the Wnt/β-catenin pathway and increased CSC-like properties compared with paclitaxel-sensitive 5637 cells. Paclitaxel sensitivity diminishes in 5637 cells after β-catenin overexpression or when they are grown as tumorspheres, enriched for the CSC-like phenotype. Additionally, downregulation of β-catenin or inhibition with XAV939 sensitizes HT1197 cells to paclitaxel. Moreover, a subset of muscle-invasive bladder carcinomas shows aberrant expression of β-catenin that associates with positive expression of the CSC marker ALDH1A1. In conclusion, we demonstrate that Wnt/β-catenin signaling contributes to paclitaxel resistance in bladder cancer cells with CSC-like properties. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

19 pages, 3398 KiB  
Article
Apoptosis Pathways Triggered by a Potent Antiproliferative Hybrid Chalcone on Human Melanoma Cells
by Irene Rodríguez, Ester Saavedra, Henoc del Rosario, Juan Perdomo, José Quintana, Filippo Prencipe, Paola Oliva, Romeo Romagnoli and Francisco Estévez
Int. J. Mol. Sci. 2021, 22(24), 13462; https://doi.org/10.3390/ijms222413462 - 15 Dec 2021
Cited by 9 | Viewed by 2249
Abstract
The World Health Organization reported that approximately 324,000 new cases of melanoma skin cancer were diagnosed worldwide in 2020. The incidence of melanoma has been increasing over the past decades. Targeting apoptotic pathways is a potential therapeutic strategy in the transition to preclinical [...] Read more.
The World Health Organization reported that approximately 324,000 new cases of melanoma skin cancer were diagnosed worldwide in 2020. The incidence of melanoma has been increasing over the past decades. Targeting apoptotic pathways is a potential therapeutic strategy in the transition to preclinical models and clinical trials. Some naturally occurring products and synthetic derivatives are apoptosis inducers and may represent a realistic option in the fight against the disease. Thus, chalcones have received considerable attention due to their potential cytotoxicity against cancer cells. We have previously reported a chalcone containing an indole and a pyridine heterocyclic rings and an α-bromoacryloylamido radical which displays potent antiproliferative activity against several tumor cell lines. In this study, we report that this chalcone is a potent apoptotic inducer for human melanoma cell lines SK-MEL-1 and MEL-HO. Cell death was associated with mitochondrial cytochrome c release and poly(ADP-ribose) polymerase cleavage and was prevented by a non-specific caspase inhibitor. Using SK-MEL-1 as a model, we found that the mechanism of cell death involves (i) the generation of reactive oxygen species, (ii) activation of the extrinsic and intrinsic apoptotic and mitogen-activated protein kinase pathways, (iii) upregulation of TRAIL, DR4 and DR5, (iv) downregulation of p21Cip1/WAF1 and, inhibition of the NF-κB pathway. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

16 pages, 5339 KiB  
Article
The Preliminary Study on the Proapoptotic Effect of Reduced Graphene Oxide in Breast Cancer Cell Lines
by Rafał Krętowski, Agata Jabłońska-Trypuć and Marzanna Cechowska-Pasko
Int. J. Mol. Sci. 2021, 22(22), 12593; https://doi.org/10.3390/ijms222212593 - 22 Nov 2021
Cited by 11 | Viewed by 2009
Abstract
Breast cancer is the most common cancer diagnosed in women, however traditional therapies have several side effects. This has led to an urgent need to explore novel drug approaches to treatment strategies such as graphene-based nanomaterials such as reduced graphene oxide (rGO). It [...] Read more.
Breast cancer is the most common cancer diagnosed in women, however traditional therapies have several side effects. This has led to an urgent need to explore novel drug approaches to treatment strategies such as graphene-based nanomaterials such as reduced graphene oxide (rGO). It was noticed as a potential drug due to its target selectivity, easy functionalisation, chemisensitisation, and high drug-loading capacity. rGO is widely used in many fields, including biological and biomedical, due to its unique physicochemical properties. However, the possible mechanisms of rGO toxicity remain unclear. In this paper, we present findings on the cytotoxic and antiproliferative effects of rGO and its ability to induce oxidative stress and apoptosis of breast cancer cell lines. We indicate that rGO induced time- and dose-dependent cytotoxicity in MDA-MB-231 and ZR-75-1 cell lines, but not in T-47D, MCF-7, Hs 578T cell lines. In rGO-treated MDA-MB-231 and ZR-75-1 cell lines, we noticed increased induction of apoptosis and necrosis. In addition, rGO has been found to cause oxidative stress, reduce proliferation, and induce structural changes in breast cancer cells. Taken together, these studies provide new insight into the mechanism of oxidative stress and apoptosis in breast cancer cells. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

15 pages, 5449 KiB  
Article
RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation
by Maria Feoktistova, Roman Makarov, Amir S. Yazdi and Diana Panayotova-Dimitrova
Int. J. Mol. Sci. 2021, 22(22), 12459; https://doi.org/10.3390/ijms222212459 - 18 Nov 2021
Cited by 16 | Viewed by 2765
Abstract
TNF is a proinflammatory cytokine that is critical for the coordination of tissue homeostasis. RIPK1 and TRADD are the main participants in the transduction of TNF signaling. However, data on the cell fate-controlling functions of both molecules are quite controversial. Here, we address [...] Read more.
TNF is a proinflammatory cytokine that is critical for the coordination of tissue homeostasis. RIPK1 and TRADD are the main participants in the transduction of TNF signaling. However, data on the cell fate-controlling functions of both molecules are quite controversial. Here, we address the functions of RIPK1 and TRADD in TNF signaling by generating RIPK1- or TRADD-deficient human cell lines. We demonstrate that RIPK1 is relevant for TNF-induced apoptosis and necroptosis in conditions with depleted IAPs. In addition, TRADD is dispensable for necroptosis but required for apoptosis. We reveal a new possible function of TRADD as a negative regulator of NIK stabilization and subsequent ripoptosome formation. Furthermore, we show that RIPK1 and TRADD do not appear to be essential for the activation of MAPK signaling. Moreover, partially repressing NF-κB activation in both RIPK1 and TRADD KO cells does not result in sensitization to TNF alone due to the absence of NIK stabilization. Importantly, we demonstrate that RIPK1 is essential for preventing TRADD from undergoing TNF-induced ubiquitination and degradation. Taken together, our findings provide further insights into the specific functions of RIPK1 and TRADD in the regulation of TNF-dependent signaling, which controls the balance between cell death and survival. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Graphical abstract

15 pages, 2870 KiB  
Article
Arginine Methylation of hnRNPK Inhibits the DDX3-hnRNPK Interaction to Play an Anti-Apoptosis Role in Osteosarcoma Cells
by Chiao-Che Chen, Jen-Hao Yang, Shu-Ling Fu, Wey-Jinq Lin and Chao-Hsiung Lin
Int. J. Mol. Sci. 2021, 22(18), 9764; https://doi.org/10.3390/ijms22189764 - 09 Sep 2021
Cited by 9 | Viewed by 2187
Abstract
Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an RNA/DNA binding protein involved in diverse cell processes; it is also a p53 coregulator that initiates apoptosis under DNA damage conditions. However, the upregulation of hnRNPK is correlated with cancer transformation, progression, and migration, whereas the [...] Read more.
Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an RNA/DNA binding protein involved in diverse cell processes; it is also a p53 coregulator that initiates apoptosis under DNA damage conditions. However, the upregulation of hnRNPK is correlated with cancer transformation, progression, and migration, whereas the regulatory role of hnRNPK in cancer malignancy remains unclear. We previously showed that arginine methylation of hnRNPK attenuated the apoptosis of U2OS osteosarcoma cells under DNA damage conditions, whereas the replacement of endogenous hnRNPK with a methylation-defective mutant inversely enhanced apoptosis. The present study further revealed that an RNA helicase, DDX3, whose C-terminus preferentially binds to the unmethylated hnRNPK and could promote such apoptotic enhancement. Moreover, C-terminus-truncated DDX3 induced significantly less apoptosis than full-length DDX3. Notably, we also identified a small molecule that docks at the ATP-binding site of DDX3, promotes the DDX3-hnRNPK interaction, and induces further apoptosis. Overall, we have shown that the arginine methylation of hnRNPK suppresses the apoptosis of U2OS cells via interfering with DDX3–hnRNPK interaction. On the other hand, DDX3–hnRNPK interaction with a proapoptotic role may serve as a target for promoting apoptosis in osteosarcoma cells. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

14 pages, 37040 KiB  
Article
circRNA-Mediated Inhibin–Activin Balance Regulation in Ovarian Granulosa Cell Apoptosis and Follicular Atresia
by Mengnan Ma, Huiming Wang, Yi Zhang, Jinbi Zhang, Jingge Liu and Zengxiang Pan
Int. J. Mol. Sci. 2021, 22(17), 9113; https://doi.org/10.3390/ijms22179113 - 24 Aug 2021
Cited by 9 | Viewed by 2161
Abstract
Ovarian granulosa cells (GC) play an essential role in the development and atresia of follicles. Emerging studies suggest that non-coding RNAs are involved in the regulation of GC apoptosis. Here, we aimed to analyze the function of ssc-circINHA-001, coded by the first exon [...] Read more.
Ovarian granulosa cells (GC) play an essential role in the development and atresia of follicles. Emerging studies suggest that non-coding RNAs are involved in the regulation of GC apoptosis. Here, we aimed to analyze the function of ssc-circINHA-001, coded by the first exon of the inhibin subunit α gene (INHA), in resisting GC apoptosis and follicular atresia by enhancing the expression of the inhibin subunit β A (INHBA) through a cluster of miRNAs. A higher expression of ssc-circINHA-001 in healthy follicles compared to early atretic follicles was detected by qRT-PCR. Its circular structure was confirmed by RNase R treatment and reversed PCR. The function of ssc-circINHA-001 in GC resistance to apoptosis was detected by in vitro transfection of its si-RNA. Furthermore, the dual-luciferase reporter assay suggested that ssc-circINHA-001 adsorbed three miRNAs, termed miR-214-5p, miR-7144-3p, and miR-9830-5p, which share the common target INHBA. A low expression of ssc-circINHA-001 increased the levels of the free miRNAs, inhibited INHBA expression, and thus raised GCs apoptosis through a shift from the secretion of activin to that of inhibin. Our study demonstrated the existence of a circRNA–microRNAs–INHBA regulatory axis in follicular GC apoptosis and provides insight into the relationship between circRNA function and its coding gene in inhibin/activin balance and ovarian physiological functions. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

22 pages, 9356 KiB  
Article
Mitochondrial Dysfunction and Alterations in Mitochondrial Permeability Transition Pore (mPTP) Contribute to Apoptosis Resistance in Idiopathic Pulmonary Fibrosis Fibroblasts
by Erika Rubí Luis-García, Carina Becerril, Alfonso Salgado-Aguayo, Omar Emiliano Aparicio-Trejo, Yair Romero, Edgar Flores-Soto, Criselda Mendoza-Milla, Martha Montaño, Victoria Chagoya, José Pedraza-Chaverri, Mohammed El Hafidi, Marisol Orozco-Ibarra, Annie Pardo and Moisés Selman
Int. J. Mol. Sci. 2021, 22(15), 7870; https://doi.org/10.3390/ijms22157870 - 23 Jul 2021
Cited by 19 | Viewed by 3483
Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by increased activation of fibroblasts/myofibroblasts. Previous reports have shown that IPF fibroblasts are resistant to apoptosis, but the mechanisms remain unclear. Since inhibition of the mitochondrial permeability transition pore (mPTP) has been implicated in [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by increased activation of fibroblasts/myofibroblasts. Previous reports have shown that IPF fibroblasts are resistant to apoptosis, but the mechanisms remain unclear. Since inhibition of the mitochondrial permeability transition pore (mPTP) has been implicated in the resistance to apoptosis, in this study, we analyzed the role of mitochondrial function and the mPTP on the apoptosis resistance of IPF fibroblasts under basal conditions and after mitomycin C-induced apoptosis. We measured the release of cytochrome c, mPTP opening, mitochondrial calcium release, oxygen consumption, mitochondrial membrane potential, ADP/ATP ratio, ATP concentration, and mitochondrial morphology. We found that IPF fibroblasts were resistant to mitomycin C-induced apoptosis and that calcium, a well-established activator of mPTP, is decreased as well as the release of pro-apoptotic proteins such as cytochrome c. Likewise, IPF fibroblasts showed decreased mitochondrial function, while mPTP was less sensitive to ionomycin-induced opening. Although IPF fibroblasts did not present changes in the mitochondrial membrane potential, we found a fragmented mitochondrial network with scarce, thinned, and disordered mitochondria with reduced ATP levels. Our findings demonstrate that IPF fibroblasts are resistant to mitomycin C-induced apoptosis and that altered mPTP opening contributes to this resistance. In addition, IPF fibroblasts show mitochondrial dysfunction evidenced by a decrease in respiratory parameters. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

Review

Jump to: Research

15 pages, 2449 KiB  
Review
Restoring TRAILR2/DR5-Mediated Activation of Apoptosis upon Endoplasmic Reticulum Stress as a Therapeutic Strategy in Cancer
by Rocío Mora-Molina and Abelardo López-Rivas
Int. J. Mol. Sci. 2022, 23(16), 8987; https://doi.org/10.3390/ijms23168987 - 12 Aug 2022
Cited by 5 | Viewed by 2272
Abstract
The uncontrolled proliferation of malignant cells in growing tumors results in the generation of different stressors in the tumor microenvironment, such as nutrient shortage, hypoxia and acidosis, among others, that disrupt endoplasmic reticulum (ER) homeostasis and may lead to ER stress. As a [...] Read more.
The uncontrolled proliferation of malignant cells in growing tumors results in the generation of different stressors in the tumor microenvironment, such as nutrient shortage, hypoxia and acidosis, among others, that disrupt endoplasmic reticulum (ER) homeostasis and may lead to ER stress. As a response to ER stress, both normal and tumor cells launch a set of signaling pathways known as the unfolded protein response (UPR) to restore ER proteostasis and maintain cell viability and function. However, under sustained ER stress, an apoptotic cell death process can be induced and this has been the subject of different review articles, although the role of the TRAIL-R2/DR5-activated extrinsic pathway of apoptosis has not yet been thoroughly summarized. In this Review, we provide an updated overview of the molecular mechanisms regulating cell fate decisions in tumor cells undergoing ER stress and discuss the role of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) in the final outcome of UPR signaling. Particularly, we focus on the mechanisms controlling cellular FLICE-like inhibitory protein (FLIP) levels in tumor cells undergoing ER stress, which may represent a potential target for therapeutic intervention in cancer. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

14 pages, 1408 KiB  
Review
Advancements in Activating Transcription Factor 5 Function in Regulating Cell Stress and Survival
by Pameila Paerhati, Jing Liu, Zhedong Jin, Tanja Jakoš, Shunyin Zhu, Lan Qian, Jianwei Zhu and Yunsheng Yuan
Int. J. Mol. Sci. 2022, 23(13), 7129; https://doi.org/10.3390/ijms23137129 - 27 Jun 2022
Cited by 6 | Viewed by 2611
Abstract
Activating transcription factor 5 (ATF5) belongs to the activating transcription factor/cyclic adenosine monophosphate (cAMP) response element-binding protein family of basic region leucine zipper transcription factors. ATF5 plays an important role in cell stress regulation and is involved in cell differentiation and survival, as [...] Read more.
Activating transcription factor 5 (ATF5) belongs to the activating transcription factor/cyclic adenosine monophosphate (cAMP) response element-binding protein family of basic region leucine zipper transcription factors. ATF5 plays an important role in cell stress regulation and is involved in cell differentiation and survival, as well as centrosome maintenance and development. Accumulating evidence demonstrates that ATF5 plays an oncogenic role in cancer by regulating gene expressions involved in tumorigenesis and tumor survival. Recent studies have indicated that ATF5 may also modify the gene expressions involved in other diseases. This review explores in detail the regulation of ATF5 expression and signaling pathways and elucidates the role of ATF5 in cancer biology. Furthermore, an overview of putative therapeutic strategies that can be used for restoring aberrant ATF5 activity in different cancer types is provided. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

26 pages, 4301 KiB  
Review
Apoptosis during ZIKA Virus Infection: Too Soon or Too Late?
by Jonathan Turpin, Daed El Safadi, Grégorie Lebeau, Morgane Krejbich, Camille Chatelain, Philippe Desprès, Wildriss Viranaïcken and Pascale Krejbich-Trotot
Int. J. Mol. Sci. 2022, 23(3), 1287; https://doi.org/10.3390/ijms23031287 - 24 Jan 2022
Cited by 14 | Viewed by 4642
Abstract
Cell death by apoptosis is a major cellular response in the control of tissue homeostasis and as a defense mechanism in the case of cellular aggression such as an infection. Cell self-destruction is part of antiviral responses, aimed at limiting the spread of [...] Read more.
Cell death by apoptosis is a major cellular response in the control of tissue homeostasis and as a defense mechanism in the case of cellular aggression such as an infection. Cell self-destruction is part of antiviral responses, aimed at limiting the spread of a virus. Although it may contribute to the deleterious effects in infectious pathology, apoptosis remains a key mechanism for viral clearance and the resolution of infection. The control mechanisms of cell death processes by viruses have been extensively studied. Apoptosis can be triggered by different viral determinants through different pathways as a result of virally induced cell stresses and innate immune responses. Zika virus (ZIKV) induces Zika disease in humans, which has caused severe neurological forms, birth defects, and microcephaly in newborns during the last epidemics. ZIKV also surprised by revealing an ability to persist in the genital tract and in semen, thus being sexually transmitted. Mechanisms of diverting antiviral responses such as the interferon response, the role of cytopathic effects and apoptosis in the etiology of the disease have been widely studied and debated. In this review, we examined the interplay between ZIKV infection of different cell types and apoptosis and how the virus deals with this cellular response. We illustrate a duality in the effects of ZIKV-controlled apoptosis, depending on whether it occurs too early or too late, respectively, in neuropathogenesis, or in long-term viral persistence. We further discuss a prospective role for apoptosis in ZIKV-related therapies, and the use of ZIKV as an oncolytic agent. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Graphical abstract

34 pages, 2566 KiB  
Review
Estrogen Receptors-Mediated Apoptosis in Hormone-Dependent Cancers
by Adele Chimento, Arianna De Luca, Paola Avena, Francesca De Amicis, Ivan Casaburi, Rosa Sirianni and Vincenzo Pezzi
Int. J. Mol. Sci. 2022, 23(3), 1242; https://doi.org/10.3390/ijms23031242 - 22 Jan 2022
Cited by 25 | Viewed by 6290
Abstract
It is known that estrogen stimulates growth and inhibits apoptosis through estrogen receptor(ER)-mediated mechanisms in many cancer cell types. Interestingly, there is strong evidence that estrogens can also induce apoptosis, activating different ER isoforms in cancer cells. It has been observed that E2/ERα [...] Read more.
It is known that estrogen stimulates growth and inhibits apoptosis through estrogen receptor(ER)-mediated mechanisms in many cancer cell types. Interestingly, there is strong evidence that estrogens can also induce apoptosis, activating different ER isoforms in cancer cells. It has been observed that E2/ERα complex activates multiple pathways involved in both cell cycle progression and apoptotic cascade prevention, while E2/ERβ complex in many cases directs the cells to apoptosis. However, the exact mechanism of estrogen-induced tumor regression is not completely known. Nevertheless, ERs expression levels of specific splice variants and their cellular localization differentially affect outcome of estrogen-dependent tumors. The goal of this review is to provide a general overview of current knowledge on ERs-mediated apoptosis that occurs in main hormone dependent-cancers. Understanding the molecular mechanisms underlying the induction of ER-mediated cell death will be useful for the development of specific ligands capable of triggering apoptosis to counteract estrogen-dependent tumor growth. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

16 pages, 1017 KiB  
Review
Apoptosis Disorder, a Key Pathogenesis of HCMV-Related Diseases
by Zhongjie Yu, Yashuo Wang, Lili Liu, Xianjuan Zhang, Shasha Jiang and Bin Wang
Int. J. Mol. Sci. 2021, 22(8), 4106; https://doi.org/10.3390/ijms22084106 - 15 Apr 2021
Cited by 8 | Viewed by 2524
Abstract
Human cytomegalovirus (HCMV) belongs to the β-herpesvirus family, which is transmitted in almost every part of the world and is carried by more than 90% of the general population. Increasing evidence indicates that HCMV infection triggers numerous diseases by disrupting the normal physiological [...] Read more.
Human cytomegalovirus (HCMV) belongs to the β-herpesvirus family, which is transmitted in almost every part of the world and is carried by more than 90% of the general population. Increasing evidence indicates that HCMV infection triggers numerous diseases by disrupting the normal physiological activity of host cells, particularly apoptosis. Apoptosis disorder plays a key role in the initiation and development of multiple diseases. However, the relationship and molecular mechanism of HCMV-related diseases and apoptosis have not yet been systematically summarized. This review aims to summarize the role of apoptosis in HCMV-related diseases and provide an insight into the molecular mechanism of apoptosis induced by HCMV infection. We summarize the literature on HCMV-related diseases and suggest novel strategies for HCMV treatment by regulating apoptosis. Full article
(This article belongs to the Special Issue Cell Apoptosis)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-21
Back to TopTop