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Cellular Stress in Cancer Progression, Drug Resistance and Treatment

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

Deadline for manuscript submissions: closed (30 November 2018) | Viewed by 78432

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Dr. Denis Collins

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Guest Editor

Cancer Biotherapeutics, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
Interests: signal transduction in cancer; tumour-immune interactions; the mechanisms of resistance to small molecules; monoclonal antibody (mAb)-targeted therapies in cancer; the impact of somatic mutations on targeted therapy responses; immune-modulatory therapies and stress-related cell signaling pathways

Dr. Eva Szegezdi

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Guest Editor

Medical Oncology Unit, Comprehensive Cancer Center, Foundation A. Gemelli Policlinic IRCCS, 00168 Rome, Italy
Interests: death receptors; apoptosis; cell death signalling; leukemia; leukemic stem cells; tumour-microenvironment interaction; drug resistance

Special Issue Information

Dear Colleagues,

Cellular stress is an inherent feature of carcinogenesis, from the start of malignant transformation throughout tumour progression to drug resistance. The normal cell stress response engages a number of checkpoints that can: 1) arrest the cell cycle temporarily to allow repair; 2) permanently arrest the cell cycle (senescence); or 3) initiate cell death. Correct functioning of these responses is essential for tumour suppression, meaning they are often aberrant in cancer.

Cellular stress pathways are triggered in malignant cells both by inherent processes in the malignant cells, such as oncogenic stress, insufficient nutrient and oxygen supply, DNA damage and endoplasmic reticulum stress due to, for example, accumulating mutant proteins as well as by extrinsic factors, such as chemotherapeutics. The cellular stress response of the tumour cells can also impact on the tumour microenvironment, including the residing the immune response against the tumour and inflammation, an area that is now at the forefront in anti-cancer therapeutic strategies.

The importance of these cell stress pathways in cancer is increasingly recognized in recent research, both as a driver of carcinogenesis and as a target for therapy. The aim of this Special Issue is to provide an updated overview of the current progress in the field and highlight perspectives and challenges for the future and invites contributions from all areas related to cellular stress pathways in cancer development, how they impact on drug resistance and may be exploited for therapy.

Dr. Denis Collins
Dr. Eva Szegezdi
Guest Editors

Manuscript Submission Information

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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.

Published Papers (12 papers)

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Research

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19 pages, 2519 KiB

Open AccessArticle

Functional Interaction of Hypoxia-Inducible Factor 2-Alpha and Autophagy Mediates Drug Resistance in Colon Cancer Cells

by Abril Saint-Martin, Jacobo Martínez-Ríos, M. Cristina Castañeda-Patlán, Miguel Angel Sarabia-Sánchez, Nydia Tejeda-Muñoz, Alberto Chinney-Herrera, Gloria Soldevila, Roberto Benelli, Paula Santoyo-Ramos, Alessandro Poggi and Martha Robles-Flores

Cancers 2019, 11(6), 755; https://doi.org/10.3390/cancers11060755 - 30 May 2019

Cited by 15 | Viewed by 4872

Abstract

Hypoxia and the accumulation of hypoxia-inducible factors (HIFs) in tumors have been associated with therapeutic resistance and with autophagy establishment. We examined the effects of stable knockdown of HIF-1α or HIF-2α expression on autophagy and drug resistance in colon cancer cells. We found that under normoxic conditions, malignant cells exhibit increased basal levels of autophagy, compared with non-malignant cells, in addition to the previously reported coexpression of HIF-1α and HIF-2α. Knockdown of HIF-1α or HIF-2α expression resulted in increased autophagic and apoptotic cell death, indicating that the survival of cells is HIF-dependent. Cytotoxic-induced cell death was significantly increased by knockdown of HIFs but not by autophagy inhibition. Strikingly, although malignancy-resistant cells were sensitized to death by nutrient stress, the combination with HIF-2α depletion, but not with HIF-1α depletion, induced severe cell death. Oxidative stress levels were significantly increased as a result of HIF-2α specific inhibition or silencing suggesting that this may contribute to sensitize cells to death. The in vitro results were confirmed in vivo using a xenograft mouse model. We found that coordinated autophagy and mTOR inhibition enhanced cell death and induced tumor remission only in HIF-2α-silenced cells. Finally, using a specific HIF-2α inhibitor alone or in combination with drugs in patient-derived primary colon cancer cells, overcame their resistance to 5-FU or CCI-779, thus emphasizing the crucial role played by HIF-2α in promoting resistance and cell survival. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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16 pages, 7080 KiB

Open AccessArticle

Combination Therapy of Chloroquine and C₂-Ceramide Enhances Cytotoxicity in Lung Cancer H460 and H1299 Cells

by Han-Lin Chou, Yi-Hsiung Lin, Wangta Liu, Chang-Yi Wu, Ruei-Nian Li, Hurng-Wern Huang, Chi-Hsien Chou, Shean-Jaw Chiou and Chien-Chih Chiu

Cancers 2019, 11(3), 370; https://doi.org/10.3390/cancers11030370 - 15 Mar 2019

Cited by 23 | Viewed by 4392

Abstract

Non-small cell lung cancer (NSCLC) is a type of malignant cancer, and 85% of metastatic NSCLC patients have a poor prognosis. C₂-ceramide induces G2/M phase arrest and cytotoxicity in NSCLC cells. In this study, the autophagy-inducing effect of C₂-ceramide was demonstrated, and cotreatment with the autophagy inhibitor chloroquine (CQ) was investigated in NSCLC H460 and H1299 cells. The results suggested that C₂-ceramide exhibited dose-dependent anticancer effects in H460 and H1299 cells and autophagy induction. Zebrafish-based acridine orange staining confirmed the combined effects in vivo. Importantly, the combination of a sublethal dose of C₂-ceramide and CQ resulted in additive cytotoxicity and autophagy in both cell lines. Alterations of related signaling factors, including Src and SIRT1 inhibition and activation of the autophagic regulators LAMP2 and LC3-I/II, contributed to the autophagy-dependent apoptosis. We found that C₂-ceramide continuously initiated autophagy; however, CQ inhibited autophagosome maturation and degradation during autophagy progression. Accumulated and non-degraded autophagosomes increased NSCLC cell stress, eventually leading to cell death. This study sheds light on improvements to NSCLC chemotherapy to reduce the chemotherapy dose and NSCLC patient burden. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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14 pages, 3093 KiB

Open AccessArticle

HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells

by Martina S. J. McDermott, Neil Conlon, Brigid C. Browne, Adam Szabo, Naoise C. Synnott, Neil A. O’Brien, Michael J. Duffy, John Crown and Norma O’Donovan

Cancers 2019, 11(2), 197; https://doi.org/10.3390/cancers11020197 - 08 Feb 2019

Cited by 19 | Viewed by 4774

Abstract

Prolonged treatment of HER2 positive breast cancer cells with tyrosine kinase inhibitors (TKIs) leads to the emergence of acquired resistance. However, the effects of continuous TKI exposure on cell fate, and the steps leading to the acquisition of a resistant phenotype are poorly understood. To explore this, we exposed five HER2 positive cells lines to HER2 targeted therapies for periods of up to 4 weeks and examined senescence associated β-galactosidase (SA-β-gal) activity together with additional markers of senescence. We found that lapatinib treatment resulted in phenotypic alterations consistent with a senescent phenotype and strong SA-β-gal activity in HER2-positive cell lines. Lapatinib-induced senescence was associated with elevated levels of p15 and p27 but was not dependent on the expression of p16 or p21. Restoring wild type p53 activity either by transfection or by treatment with APR-246, a molecule which reactivates mutant p53, blocked lapatinib-induced senescence and caused increased cell death. In contrast to lapatinib, SA-β-gal activity was not induced by exposing the cells to trastuzumab as a single agent but co-administration of lapatinib and trastuzumab induced senescence, as did treatment of the cells with the irreversible HER2 TKIs neratinib and afatinib. Neratinib- and afatinib-induced senescence was not reversed by removing the drug whereas lapatinib-induced senescence was reversible. In summary, therapy-induced senescence represents a novel mechanism of action of HER2 targeting agents and may be a potential pathway for the emergence of resistance. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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15 pages, 2627 KiB

Open AccessArticle

High-Throughput Screening Identified Compounds Sensitizing Tumor Cells to Glucose Starvation in Culture and VEGF Inhibitors In Vivo

by Ran Marciano, Manu Prasad, Tal Ievy, Sapir Tzadok, Gabriel Leprivier, Moshe Elkabets and Barak Rotblat

Cancers 2019, 11(2), 156; https://doi.org/10.3390/cancers11020156 - 30 Jan 2019

Cited by 14 | Viewed by 5342

Abstract

Tumor cells utilize glucose to fuel their anabolic needs, including rapid proliferation. However, due to defective vasculature and increased glucose uptake, tumor cells must overcome glucose deprivation. Accordingly, tumor cells depend on cellular pathways promoting survival under such conditions. Targeting these survival mechanisms can thus serve as a new therapeutic strategy in oncology. As such, we sought to identify small-molecule inhibitors which sensitize tumor cells to glucose starvation by high-throughput drug screening in vitro. Specifically, we searched for inhibitors that selectively killed tumor cells growing in glucose-free but not in normal medium. This phenotypic drug screen of 7000 agents with MCF7 cells led to the identification of 67 potential candidates, 31 of which were validated individually. Among the identified compounds, we found a high number of compounds known to target mitochondria. The efficacies of two of the identified compounds, QNZ (EVP4593) and papaverine, were validated in four different tumor cell lines. We found that these agents inhibited the mTOR(Mechamistic\Mammilian Target of Rapamycin) pathway in tumor cells growing under glucose starvation, but not under normal conditions. The results were validated and confirmed in vivo, with QNZ and papaverine exhibiting superior antitumor activity in a tumor xenograft model when combined with the VEGF inhibitor bevacizumab (avastin). Administering these drug combinations (i.e., avastin and papaverine, and avastin and QNZ) led to significant reductions in proliferation and mTOR activity of the aggressive DLD1 colon cell line in mice. Given our findings, we propose that compounds targeting metabolically challenged tumors, such as inhibitors of mitochondrial activity, be considered as a therapeutic strategy in cancer. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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19 pages, 4746 KiB

Open AccessArticle

The PERK Branch of the Unfolded Protein Response Promotes DLL4 Expression by Activating an Alternative Translation Mechanism

by Manon Jaud, Céline Philippe, Loic Van Den Berghe, Christèle Ségura, Laurent Mazzolini, Stéphane Pyronnet, Henrik Laurell and Christian Touriol

Cancers 2019, 11(2), 142; https://doi.org/10.3390/cancers11020142 - 25 Jan 2019

Cited by 12 | Viewed by 4772

Abstract

Delta-like 4 (DLL4) is a pivotal endothelium specific Notch ligand that has been shown to function as a regulating factor during physiological and pathological angiogenesis. DLL4 functions as a negative regulator of angiogenic branching and sprouting. Interestingly, Dll4 is with Vegf-a one of the few examples of haplo-insufficiency, resulting in obvious vascular abnormalities and in embryonic lethality. These striking phenotypes are a proof of concept of the crucial role played by the bioavailability of VEGF and DLL4 during vessel patterning and that there must be a very fine-tuning of DLL4 expression level. However, to date the expression regulation of this factor was poorly studied. In this study, we showed that the DLL4 5′-UTR harbors an Internal Ribosomal Entry Site (IRES) that, in contrast to cap-dependent translation, was efficiently utilized in cells subjected to several stresses including hypoxia and endoplasmic reticulum stress (ER stress). We identified PERK, a kinase activated by ER stress, as the driver of DLL4 IRES-mediated translation, and hnRNP-A1 as an IRES-Trans-Acting Factor (ITAF) participating in the IRES-dependent translation of DLL4 during endoplasmic reticulum stress. The presence of a stress responsive internal ribosome entry site in the DLL4 msRNA suggests that the process of alternative translation initiation, by controlling the expression of this factor, could have a crucial role in the control of endothelial tip cell function. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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21 pages, 7007 KiB

Open AccessArticle

Fenofibrate Augments the Sensitivity of Drug-Resistant Prostate Cancer Cells to Docetaxel

by Marcin Luty, Katarzyna Piwowarczyk, Anna Łabędź-Masłowska, Tomasz Wróbel, Małgorzata Szczygieł, Jessica Catapano, Grażyna Drabik, Damian Ryszawy, Sylwia Kędracka-Krok, Zbigniew Madeja, Maciej Siedlar, Martyna Elas and Jarosław Czyż

Cancers 2019, 11(1), 77; https://doi.org/10.3390/cancers11010077 - 11 Jan 2019

Cited by 23 | Viewed by 4416

Abstract

Metronomic agents reduce the effective doses and adverse effects of cytostatics in cancer chemotherapy. Therefore, they can enhance the treatment efficiency of drug-resistant cancers. Cytostatic and anti-angiogenic effects of fenofibrate (FF) suggest that it can be used for the metronomic chemotherapy of drug-resistant prostate tumors. To estimate the effect of FF on the drug-resistance of prostate cancer cells, we compared the reactions of naïve and drug-resistant cells to the combined treatment with docetaxel (DCX)/mitoxantrone (MTX) and FF. FF sensitized drug-resistant DU145 and PC3 cells to DCX and MTX, as illustrated by their reduced viability and invasive potential observed in the presence of DCX/MTX and FF. The synergy of the cytostatic activities of both agents was accompanied by the inactivation of P-gp-dependent efflux, dysfunction of the microtubular system, and induction of polyploidy in DCX-resistant cells. Chemical inhibition of PPARα- and reactive oxygen species (ROS)-dependent pathways by GW6471 and N-acetyl-L-cysteine, respectively, had no effect on cell sensitivity to combined DCX/FF treatment. Instead, we observed the signs of adenosine triphosphate (ATP) deficit and autophagy in DCX/FF-treated drug-resistant cells. Furthermore, the cells that had been permanently propagated under DCX- and DCX/FF-induced stress did not acquire DCX/FF-resistance. Instead, relatively slow proliferation of DCX-resistant cells was efficiently inhibited by FF. Collectively, our observations show that FF reduces the effective doses of DCX by interfering with the drug resistance and energy metabolism of prostate cancer cells. Concomitantly, it impairs the chemotherapy-induced microevolution and expansion of DCX/FF-resistant cells. Therefore, FF can be applied as a metronomic agent to enhance the efficiency of palliative chemotherapy of prostate cancer. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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Review

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23 pages, 2423 KiB

Open AccessReview

Contribution of Mitochondrial Ion Channels to Chemo-Resistance in Cancer Cells

by Roberta Peruzzo and Ildiko Szabo

Cancers 2019, 11(6), 761; https://doi.org/10.3390/cancers11060761 - 31 May 2019

Cited by 31 | Viewed by 5700

Abstract

Mitochondrial ion channels are emerging oncological targets, as modulation of these ion-transporting proteins may impact on mitochondrial membrane potential, efficiency of oxidative phosphorylation and reactive oxygen production. In turn, these factors affect the release of cytochrome c, which is the point of no return during mitochondrial apoptosis. Many of the currently used chemotherapeutics induce programmed cell death causing damage to DNA and subsequent activation of p53-dependent pathways that finally leads to cytochrome c release from the mitochondrial inter-membrane space. The view is emerging, as summarized in the present review, that ion channels located in this organelle may account in several cases for the resistance that cancer cells can develop against classical chemotherapeutics, by preventing drug-induced apoptosis. Thus, pharmacological modulation of these channel activities might be beneficial to fight chemo-resistance of different types of cancer cells. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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25 pages, 1935 KiB

Open AccessEditor’s ChoiceReview

Emerging Roles of the Endoplasmic Reticulum Associated Unfolded Protein Response in Cancer Cell Migration and Invasion

by Celia Maria Limia, Chloé Sauzay, Hery Urra, Claudio Hetz, Eric Chevet and Tony Avril

Cancers 2019, 11(5), 631; https://doi.org/10.3390/cancers11050631 - 06 May 2019

Cited by 61 | Viewed by 8089

Abstract

Endoplasmic reticulum (ER) proteostasis is often altered in tumor cells due to intrinsic (oncogene expression, aneuploidy) and extrinsic (environmental) challenges. ER stress triggers the activation of an adaptive response named the Unfolded Protein Response (UPR), leading to protein translation repression, and to the improvement of ER protein folding and clearance capacity. The UPR is emerging as a key player in malignant transformation and tumor growth, impacting on most hallmarks of cancer. As such, the UPR can influence cancer cells’ migration and invasion properties. In this review, we overview the involvement of the UPR in cancer progression. We discuss its cross-talks with the cell migration and invasion machinery. Specific aspects will be covered including extracellular matrix (ECM) remodeling, modification of cell adhesion, chemo-attraction, epithelial-mesenchymal transition (EMT), modulation of signaling pathways associated with cell mobility, and cytoskeleton remodeling. The therapeutic potential of targeting the UPR to treat cancer will also be considered with specific emphasis in the impact on metastasis and tissue invasion. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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17 pages, 1027 KiB

Open AccessEditor’s ChoiceReview

Acquired Resistance to Antibody-Drug Conjugates

by Denis M. Collins, Birgit Bossenmaier, Gwendlyn Kollmorgen and Gerhard Niederfellner

Cancers 2019, 11(3), 394; https://doi.org/10.3390/cancers11030394 - 20 Mar 2019

Cited by 82 | Viewed by 8564

Abstract

Antibody-drug conjugates (ADCs) combine the tumor selectivity of antibodies with the potency of cytotoxic small molecules thereby constituting antibody-mediated chemotherapy. As this inherently limits the adverse effects of the chemotherapeutic, such approaches are heavily pursued by pharma and biotech companies and have resulted in four FDA (Food and Drug Administration)-approved ADCs. However, as with other cancer therapies, durable responses are limited by the fact that under cell stress exerted by these drugs, tumors can acquire mechanisms of escape. Resistance can develop against the antibody component of ADCs by down-regulation/mutation of the targeted cell surface antigen or against payload toxicity by up-regulation of drug efflux transporters. Unique resistance mechanisms specific for the mode of action of ADCs have also emerged, like altered internalization or cell surface recycling of the targeted tumor antigen, changes in the intracellular routing or processing of ADCs, and impaired release of the toxic payload into the cytosol. These evasive changes are tailored to the specific nature and interplay of the three ADC constituents: the antibody, the linker, and the payload. Hence, they do not necessarily endow broad resistance to ADC therapy. This review summarizes preclinical and clinical findings that shed light on the mechanisms of acquired resistance to ADC therapies. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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14 pages, 613 KiB

Open AccessReview

Role of Extracellular Vesicles (EVs) in Cell Stress Response and Resistance to Cancer Therapy

by Clodagh P. O’Neill, Katie E. Gilligan and Róisín M. Dwyer

Cancers 2019, 11(2), 136; https://doi.org/10.3390/cancers11020136 - 24 Jan 2019

Cited by 73 | Viewed by 9856

Abstract

Extracellular vesicles (EVs) are nanosized particles released by all cells that have been heralded as novel regulators of cell-to-cell communication. It is becoming increasingly clear that in response to a variety of stress conditions, cells employ EV-mediated intercellular communication to transmit a pro-survival message in the tumor microenvironment and beyond, supporting evasion of cell death and transmitting resistance to therapy. Understanding changes in EV cargo and secretion pattern during cell stress may uncover novel, targetable mechanisms underlying disease progression, metastasis and resistance to therapy. Further, the profile of EVs released into the circulation may provide a circulating biomarker predictive of response to therapy and indicative of microenvironmental conditions linked to disease progression, such as hypoxia. Continued progress in this exciting and rapidly expanding field of research will be dependent upon widespread adoption of transparent reporting standards and implementation of guidelines to establish a consensus on methods of EV isolation, characterisation and nomenclature employed. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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21 pages, 1174 KiB

Open AccessEditor’s ChoiceReview

Targeting Proteotoxic Stress in Cancer: A Review of the Role that Protein Quality Control Pathways Play in Oncogenesis

by Matthew Ho Zhi Guang, Emma L. Kavanagh, Luke Paul Dunne, Paul Dowling, Li Zhang, Sinéad Lindsay, Despina Bazou, Chia Yin Goh, Cathal Hanley, Giada Bianchi, Kenneth C. Anderson, Peter O’Gorman and Amanda McCann

Cancers 2019, 11(1), 66; https://doi.org/10.3390/cancers11010066 - 09 Jan 2019

Cited by 69 | Viewed by 8231

Abstract

Despite significant advances in cancer diagnostics and therapeutics the majority of cancer unfortunately remains incurable, which has led to continued research to better understand its exceptionally diverse biology. As a result of genomic instability, cancer cells typically have elevated proteotoxic stress. Recent appreciation of this functional link between the two secondary hallmarks of cancer: aneuploidy (oxidative stress) and proteotoxic stress, has therefore led to the development of new anticancer therapies targeting this emerging “Achilles heel” of malignancy. This review highlights the importance of managing proteotoxic stress for cancer cell survival and provides an overview of the integral role proteostasis pathways play in the maintenance of protein homeostasis. We further review the efforts undertaken to exploit proteotoxic stress in multiple myeloma (as an example of a hematologic malignancy) and triple negative breast cancer (as an example of a solid tumor), and give examples of: (1) FDA-approved therapies in routine clinical use; and (2) promising therapies currently in clinical trials. Finally, we provide new insights gleaned from the use of emerging technologies to disrupt the protein secretory pathway and repurpose E3 ligases to achieve targeted protein degradation. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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21 pages, 1351 KiB

Open AccessFeature PaperReview

The Unfolded Protein Response in Breast Cancer

by Eoghan P. McGrath, Susan E. Logue, Katarzyna Mnich, Shane Deegan, Richard Jäger, Adrienne M. Gorman and Afshin Samali

Cancers 2018, 10(10), 344; https://doi.org/10.3390/cancers10100344 - 21 Sep 2018

Cited by 61 | Viewed by 7497

Abstract

In 2018, in the US alone, it is estimated that 268,670 people will be diagnosed with breast cancer, and that 41,400 will die from it. Since breast cancers often become resistant to therapies, and certain breast cancers lack therapeutic targets, new approaches are urgently required. A cell-stress response pathway, the unfolded protein response (UPR), has emerged as a promising target for the development of novel breast cancer treatments. This pathway is activated in response to a disturbance in endoplasmic reticulum (ER) homeostasis but has diverse physiological and disease-specific functions. In breast cancer, UPR signalling promotes a malignant phenotype and can confer tumours with resistance to widely used therapies. Here, we review several roles for UPR signalling in breast cancer, highlighting UPR-mediated therapy resistance and the potential for targeting the UPR alone or in combination with existing therapies. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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