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Cancers
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Deregulation of Cell Death in Cancer
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Deregulation of Cell Death in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 31744

Special Issue Editors

Prof. Dr. Lucia Altucci

E-Mail Website
Guest Editor
Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Napoli, Italy
Interests: leukaemia; epigenetic; personalized medicine; networking approaches
Special Issues, Collections and Topics in MDPI journals
Dr. Vincenzo Carafa

E-Mail Website
Co-Guest Editor
Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Napoli, Italy
Interests: programmed cell death; apoptosis; leukaemia; epigenetic; acetylation; sirtuins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The correct balance between the production of "new" and the elimination of "old" cells is a central point of an important biological question under investigation, given that many pathologies arise through a disruption of homeostasis. Evading apoptosis is one of the well-identified hallmarks of cancer and is the principal characteristic of tumor cells, responsible for cancer initiation, progression, and metastasization processes.

Apoptosis is an extremely organized programmed process in which the coordination of specific well-described events such as the disruption of cellular membranes, DNA fragmentation, cell shrinking, and removal of cellular debris represent a fundamental condition to avoid immune response.

Different programmed cell deaths (PCDs) have been described and recently classified. The identification of the molecular mechanisms of PCD plays a pivotal role in our understanding of cancer. Considering that i) conventional diagnosis methods are not efficient for early-stage cancer detection, and ii) the silencing of the apoptotic responses might be contributing to the treatment resistance observed in many tumors, the study of proteins involved in PCD pathways and how it is possible to regulate, modulate, and restore PCD equilibrium might represent a useful approach in anticancer therapy.

This Special Issue is aimed at presenting the latest research underlining the relationship between cancer and PCD, new insights into the cellular mechanisms involved, drug discovery, and therapeutic apoptosis-based strategies, which will allow us to gain a better understanding of the role of PCD in cancerogenesis.

Prof. Dr. Lucia Altucci
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.

Published Papers (9 papers)

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Editorial

Jump to: Research, Review

4 pages, 185 KiB  
Editorial
Deregulation of Cell Death in Cancer: Recent Highlights
by Vincenzo Carafa and Lucia Altucci
Cancers 2020, 12(12), 3517; https://doi.org/10.3390/cancers12123517 - 26 Nov 2020
Cited by 7 | Viewed by 1424
Abstract
The aim of this Special Issue on the deregulation of cell death in cancer is to bring together recent perspectives on the relationship between tumorigenesis and programmed cell death (PCD) [...] Full article
(This article belongs to the Special Issue Deregulation of Cell Death in Cancer)

Research

Jump to: Editorial, Review

21 pages, 4861 KiB  
Article
EPHA2 Interacts with DNA-PKcs in Cell Nucleus and Controls Ionizing Radiation Responses in Non-Small Cell Lung Cancer Cells
by Vitaliy O. Kaminskyy, Petra Hååg, Metka Novak, Ákos Végvári, Vasiliki Arapi, Rolf Lewensohn and Kristina Viktorsson
Cancers 2021, 13(5), 1010; https://doi.org/10.3390/cancers13051010 - 28 Feb 2021
Cited by 8 | Viewed by 2454
Abstract
Ephrin (EFN)/Erythropoietin-producing human hepatocellular receptors (Eph) signaling has earlier been reported to regulate non-small cell lung cancer (NSCLC) cell survival and cell death as well as invasion and migration. Here, the role of Ephrin type-A receptor 2 (EphA2) on the DNA damage response [...] Read more.
Ephrin (EFN)/Erythropoietin-producing human hepatocellular receptors (Eph) signaling has earlier been reported to regulate non-small cell lung cancer (NSCLC) cell survival and cell death as well as invasion and migration. Here, the role of Ephrin type-A receptor 2 (EphA2) on the DNA damage response (DDR) signaling and ionizing radiation (IR) cellular effect was studied in NSCLC cells. Silencing of EphA2 resulted in IR sensitization, with increased activation of caspase-3, PARP-1 cleavage and reduced clonogenic survival. Profiling of EphA2 expression in a NSCLC cell line panel showed a correlation to an IR refractory phenotype. EphA2 was found to be transiently and rapidly phosphorylated at Ser897 in response to IR, which was paralleled with the activation of ribosomal protein S6 kinase (RSK). Using cell fractionation, a transient increase in both total and pSer897 EphA2 in the nuclear fraction in response to IR was revealed. By immunoprecipitation and LC-MS/MS analysis of EphA2 complexes, nuclear localized EphA2 was found in a complex with DNA-PKcs. Such complex formation rapidly increased after IR but returned back to basal level within an hour. Targeting EphA2 with siRNA or by treatment with EFNA1 ligand partly reduced phosphorylation of DNA-PKcs at S2056 at early time points after IR. Thus, we report that EphA2 interacts with DNA-PKcs in the cell nucleus suggesting a novel mechanism involving the EphA2 receptor in DDR signaling and IR responsiveness. Full article
(This article belongs to the Special Issue Deregulation of Cell Death in Cancer)
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23 pages, 4940 KiB  
Article
Development of a Cationic Amphiphilic Helical Peptidomimetic (B18L) As A Novel Anti-Cancer Drug Lead
by Yuan Lyu, Steven Kopcho, Folnetti A. Alvarez, Bryson C. Okeoma and Chioma M. Okeoma
Cancers 2020, 12(9), 2448; https://doi.org/10.3390/cancers12092448 - 28 Aug 2020
Cited by 7 | Viewed by 2543
Abstract
BST-2 is a novel driver of cancer progression whose expression confers oncogenic properties to breast cancer cells. As such, targeting BST-2 in tumors may be an effective therapeutic approach against breast cancer. Here, we sought to develop potent cytotoxic anti-cancer agent using the [...] Read more.
BST-2 is a novel driver of cancer progression whose expression confers oncogenic properties to breast cancer cells. As such, targeting BST-2 in tumors may be an effective therapeutic approach against breast cancer. Here, we sought to develop potent cytotoxic anti-cancer agent using the second-generation BST-2-based anti-adhesion peptide, B18, as backbone. To this end, we designed a series of five B18-derived peptidomimetics. Among these, B18L, a cationic amphiphilic α-helical peptidomimetic, was selected as the drug lead because it displayed superior anti-cancer activity against both drug-resistant and drug-sensitive cancer cells, with minimal toxicity on normal cells. Probing mechanism of action using molecular dynamics simulations, biochemical and membrane biophysics studies, we observed that B18L binds BST-2 and possesses membranolytic characteristics. Furthermore, molecular biology studies show that B18L dysregulates cancer signaling pathways resulting in decreased Src and Erk1/2 phosphorylation, increased expression of pro-apoptotic Bcl2 proteins, caspase 3 cleavage products, as well as processing of the caspase substrate, poly (ADP-ribose) polymerase-1 (PARP-1), to the characteristic apoptotic fragment. These data indicate that through the coordinated regulation of membrane, mitochondrial and signaling events, B18L executes cancer cell death and thus has the potential to be developed into a potent and selective anti-cancer compound. Full article
(This article belongs to the Special Issue Deregulation of Cell Death in Cancer)
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25 pages, 3882 KiB  
Article
Relation of Neutrophil Gelatinase-Associated Lipocalin Overexpression to the Resistance to Apoptosis of Tumor B Cells in Chronic Lymphocytic Leukemia
by Brigitte Bauvois, Elodie Pramil, Ludovic Jondreville, Elise Chapiro, Claire Quiney, Karim Maloum, Santos A. Susin and Florence Nguyen-Khac
Cancers 2020, 12(8), 2124; https://doi.org/10.3390/cancers12082124 - 31 Jul 2020
Cited by 10 | Viewed by 2429
Abstract
The resistance to apoptosis of chronic lymphocytic leukemia (CLL) cells partly results from the deregulated production of survival signals from leukemic cells. Despite the development of new therapies in CLL, drug resistance and disease relapse still occur. Recently, neutrophil gelatinase-associated lipocalin (NGAL), a [...] Read more.
The resistance to apoptosis of chronic lymphocytic leukemia (CLL) cells partly results from the deregulated production of survival signals from leukemic cells. Despite the development of new therapies in CLL, drug resistance and disease relapse still occur. Recently, neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, has been suggested to have a critical role in the biology of tumors. Thus, we investigated the relevance of NGAL in CLL pathogenesis, analyzed the expression of its cellular receptor (NGAL-R) on malignant B cells and tested whether CLL cells are resistant to apoptosis through an autocrine process involving NGAL and NGAL-R. We observed that NGAL concentrations were elevated in the serum of CLL patients at diagnosis. After treatment (and regardless of the therapeutic regimen), serum NGAL levels normalized in CLL patients in remission but not in relapsed patients. In parallel, NGAL and NGAL-R were upregulated in leukemic cells from untreated CLL patients when compared to normal peripheral blood mononuclear cells (PBMCs), and returned to basal levels in PBMCs from patients in remission. Cultured CLL cells released endogenous NGAL. Anti-NGAL-R antibodies enhanced NGAL-R+ leukemia cell death. Conversely, recombinant NGAL protected NGAL-R+ CLL cells against apoptosis by activating a STAT3/Mcl-1 signaling pathway. Our results suggest that NGAL and NGAL-R, overexpressed in untreated CLL, participate in the deregulation of the apoptotic machinery in CLL cells, and may be potential therapeutic clues for CLL treatment. Full article
(This article belongs to the Special Issue Deregulation of Cell Death in Cancer)
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Review

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24 pages, 3472 KiB  
Review
The Two-Faced Role of SIRT6 in Cancer
by Francesco Fiorentino, Vincenzo Carafa, Gregorio Favale, Lucia Altucci, Antonello Mai and Dante Rotili
Cancers 2021, 13(5), 1156; https://doi.org/10.3390/cancers13051156 - 08 Mar 2021
Cited by 34 | Viewed by 4526
Abstract
Sirtuin 6 (SIRT6) is a NAD+-dependent nuclear deacylase and mono-ADP-ribosylase with a wide spectrum of substrates. Through its pleiotropic activities, SIRT6 modulates either directly or indirectly key processes linked to cell fate determination and oncogenesis such as DNA damage repair, metabolic [...] Read more.
Sirtuin 6 (SIRT6) is a NAD+-dependent nuclear deacylase and mono-ADP-ribosylase with a wide spectrum of substrates. Through its pleiotropic activities, SIRT6 modulates either directly or indirectly key processes linked to cell fate determination and oncogenesis such as DNA damage repair, metabolic homeostasis, and apoptosis. SIRT6 regulates the expression and activity of both pro-apoptotic (e.g., Bax) and anti-apoptotic factors (e.g., Bcl-2, survivin) in a context-depending manner. Mounting evidence points towards a double-faced involvement of SIRT6 in tumor onset and progression since the block or induction of apoptosis lead to opposite outcomes in cancer. Here, we discuss the features and roles of SIRT6 in the regulation of cell death and cancer, also focusing on recently discovered small molecule modulators that can be used as chemical probes to shed further light on SIRT6 cancer biology and proposed as potential new generation anticancer therapeutics. Full article
(This article belongs to the Special Issue Deregulation of Cell Death in Cancer)
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20 pages, 1495 KiB  
Review
The Role of Necroptosis: Biological Relevance and Its Involvement in Cancer
by Laura Della Torre, Angela Nebbioso, Hendrik G. Stunnenberg, Joost H. A. Martens, Vincenzo Carafa and Lucia Altucci
Cancers 2021, 13(4), 684; https://doi.org/10.3390/cancers13040684 - 08 Feb 2021
Cited by 25 | Viewed by 3823
Abstract
Regulated cell death mechanisms are essential for the maintenance of cellular homeostasis. Evasion of cell death is one of the most important hallmarks of cancer. Necroptosis is a caspase independent form of regulated cell death, investigated as a novel therapeutic strategy to eradicate [...] Read more.
Regulated cell death mechanisms are essential for the maintenance of cellular homeostasis. Evasion of cell death is one of the most important hallmarks of cancer. Necroptosis is a caspase independent form of regulated cell death, investigated as a novel therapeutic strategy to eradicate apoptosis resistant cancer cells. The process can be triggered by a variety of stimuli and is controlled by the activation of RIP kinases family as well as MLKL. The well-studied executor, RIPK1, is able to modulate key cellular events through the interaction with several proteins, acting as strategic crossroads of several molecular pathways. Little evidence is reported about its involvement in tumorigenesis. In this review, we summarize current studies on the biological relevance of necroptosis, its contradictory role in cancer and its function in cell fate control. Targeting necroptosis might be a novel therapeutic intervention strategy in anticancer therapies as a pharmacologically controllable event. Full article
(This article belongs to the Special Issue Deregulation of Cell Death in Cancer)
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24 pages, 849 KiB  
Review
The Great Escape: The Power of Cancer Stem Cells to Evade Programmed Cell Death
by Vanessa Castelli, Antonio Giordano, Elisabetta Benedetti, Francesco Giansanti, Massimiliano Quintiliani, Annamaria Cimini and Michele d’Angelo
Cancers 2021, 13(2), 328; https://doi.org/10.3390/cancers13020328 - 17 Jan 2021
Cited by 21 | Viewed by 3672
Abstract
Cancer is one of the primary causes of death worldwide. Tumour malignancy is related to tumor heterogeneity, which has been suggested to be due to a small subpopulation of tumor cells named cancer stem cells (CSCs). CSCs exert a key role in metastasis [...] Read more.
Cancer is one of the primary causes of death worldwide. Tumour malignancy is related to tumor heterogeneity, which has been suggested to be due to a small subpopulation of tumor cells named cancer stem cells (CSCs). CSCs exert a key role in metastasis development, tumor recurrence, and also epithelial–mesenchymal transition, apoptotic resistance, self-renewal, tumorigenesis, differentiation, and drug resistance. Several current therapies fail to eradicate tumors due to the ability of CSCs to escape different programmed cell deaths. Thus, developing CSC-selective and programmed death-inducing therapeutic approaches appears to be of primary importance. In this review, we discuss the main programmed cell death occurring in cancer and the promising CSC-targeting agents developed in recent years. Even if the reported studies are encouraging, further investigations are necessary to establish a combination of agents able to eradicate CSCs or inhibit their growth and proliferation. Full article
(This article belongs to the Special Issue Deregulation of Cell Death in Cancer)
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Graphical abstract

64 pages, 1485 KiB  
Review
Natural Products as Inducers of Non-Canonical Cell Death: A Weapon against Cancer
by Giulia Greco, Elena Catanzaro and Carmela Fimognari
Cancers 2021, 13(2), 304; https://doi.org/10.3390/cancers13020304 - 15 Jan 2021
Cited by 36 | Viewed by 5439
Abstract
Apoptosis has been considered the main mechanism induced by cancer chemotherapeutic drugs for a long time. This paradigm is currently evolving and changing, as increasing evidence pointed out that antitumor agents could trigger various non-canonical or non-apoptotic cell death types. A considerable number [...] Read more.
Apoptosis has been considered the main mechanism induced by cancer chemotherapeutic drugs for a long time. This paradigm is currently evolving and changing, as increasing evidence pointed out that antitumor agents could trigger various non-canonical or non-apoptotic cell death types. A considerable number of antitumor drugs derive from natural sources, both in their naturally occurring form or as synthetic derivatives. Therefore, it is not surprising that several natural compounds have been explored for their ability to induce non-canonical cell death. The aim of this review is to highlight the potential antitumor effects of natural products as ferroptosis, necroptosis, or pyroptosis inducers. Natural products have proven to be promising non-canonical cell death inducers, capable of overcoming cancer cells resistance to apoptosis. However, as discussed in this review, they often lack a full characterization of their antitumor activity together with an in-depth investigation of their toxicological profile. Full article
(This article belongs to the Special Issue Deregulation of Cell Death in Cancer)
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22 pages, 1197 KiB  
Review
Proteotoxic Stress and Cell Death in Cancer Cells
by Claudio Brancolini and Luca Iuliano
Cancers 2020, 12(9), 2385; https://doi.org/10.3390/cancers12092385 - 23 Aug 2020
Cited by 33 | Viewed by 4604
Abstract
To maintain proteostasis, cells must integrate information and activities that supervise protein synthesis, protein folding, conformational stability, and also protein degradation. Extrinsic and intrinsic conditions can both impact normal proteostasis, causing the appearance of proteotoxic stress. Initially, proteotoxic stress elicits adaptive responses aimed [...] Read more.
To maintain proteostasis, cells must integrate information and activities that supervise protein synthesis, protein folding, conformational stability, and also protein degradation. Extrinsic and intrinsic conditions can both impact normal proteostasis, causing the appearance of proteotoxic stress. Initially, proteotoxic stress elicits adaptive responses aimed at restoring proteostasis, allowing cells to survive the stress condition. However, if the proteostasis restoration fails, a permanent and sustained proteotoxic stress can be deleterious, and cell death ensues. Many cancer cells convive with high levels of proteotoxic stress, and this condition could be exploited from a therapeutic perspective. Understanding the cell death pathways engaged by proteotoxic stress is instrumental to better hijack the proliferative fate of cancer cells. Full article
(This article belongs to the Special Issue Deregulation of Cell Death in Cancer)
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