Apoptosis and Alternative Modes of Cell Death as Targets for Anticancer Therapy

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 31 October 2024 | Viewed by 8163

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Guest Editor
Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA
Interests: cancer; intercellular communication; autophagy; intracellular trafficking
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Special Issue Information

Dear Colleagues,

Cell death by apoptosis has long been deemed a promising target for anticancer therapy through the targeting of either of its molecular legs, i.e., the intrinsic and extrinsic pathways. For decades after its role in cancer biology was demonstrated, there has been a ceaseless search for therapeutic strategies to target this process, whether via the development of death receptor agonists such as recombinant humanized anti-receptor agonistic antibodies, small molecules aimed at specific molecular players, etc.

However, over the years, new challenges have arisen. Targeted therapies which initially showed promise in preclinical data, did not perform as well in clinical trials. Resistance to apoptosis-targeting drugs has often resulted in disease relapse and cancer mortality. These challenges, far from bringing disinterest from apoptosis as a specific and viable anti-cancer avenue, have opened researchers’ eyes to thinking about missing biological clues. Indeed, new opportunities are revealed by basic science research that shed light on connections between the apoptotic mode of cell death and alternative modes and mechanisms of cell demise, including the role of autophagy, necroptosis, ferroptosis, pyroptosis, among others. Focus has extended to new ways for considering apoptosis-based therapies within specific cellular and molecular contexts including autophagy, cancer stem cells, small RNAs, extracellular vesicles, and intercellular communication, to name just a few.

This Special Issue is intended as a showcase of the pertinence of apoptosis and alternative modes of cell death as important targets for anti-cancer therapy, which is fine-tuned by input from newly characterized associated biological processes.

Dr. Mustapha Kandouz
Guest Editor

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Keywords

  • apoptosis
  • cancer therapy
  • cell death
  • autophagy
  • necroptosis
  • ferroptosis
  • pyroptosis
  • stem cells
  • small RNAs
  • extracellular vesicles
  • intercellular communication

Published Papers (5 papers)

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Research

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19 pages, 4902 KiB  
Article
MiR-630 Promotes Radioresistance by Induction of Anti-Apoptotic Effect via Nrf2–GPX2 Molecular Axis in Head–Neck Cancer
by Guo-Rung You, Ann-Joy Cheng, Eric Yi-Liang Shen, Kang-Hsing Fan, Yi-Fang Huang, Yu-Chen Huang, Kai-Ping Chang and Joseph T. Chang
Cells 2023, 12(24), 2853; https://doi.org/10.3390/cells12242853 - 17 Dec 2023
Viewed by 1270
Abstract
Head and neck cancer (HNC) ranks among the top ten prevalent cancers worldwide. Radiotherapy stands as a pivotal treatment component for HNC; however, radioresistance in cancerous cells often leads to local recurrence, becoming a substantial factor in treatment failure. MicroRNAs (miRNAs) are compact, [...] Read more.
Head and neck cancer (HNC) ranks among the top ten prevalent cancers worldwide. Radiotherapy stands as a pivotal treatment component for HNC; however, radioresistance in cancerous cells often leads to local recurrence, becoming a substantial factor in treatment failure. MicroRNAs (miRNAs) are compact, non-coding RNAs that regulate gene expression by targeting mRNAs to inhibit protein translation. Although several studies have indicated that the dysregulation of miRNAs is intricately linked with malignant transformation, understanding this molecular family’s role in radioresistance remains limited. This study determined the role of miR-630 in regulating radiosensitivity in HNC. We discovered that miR-630 functions as an oncomiR, marked by its overexpression in HNC patients, correlating with a poorer prognosis. We further delineated the malignant function of miR-630 in HNC cells. While it had a minimal impact on cell growth, the miR-630 contributed to radioresistance in HNC cells. This result was supported by decreased cellular apoptosis and caspase enzyme activities. Moreover, miR-630 overexpression mitigated irradiation-induced DNA damage, evidenced by the reduced levels of the γ-H2AX histone protein, a marker for double-strand DNA breaks. Mechanistically, the overexpression of miR-630 decreased the cellular ROS levels and initiated Nrf2 transcriptional activity, resulting in the upregulation of the antioxidant enzyme GPX2. Thus, this study elucidates that miR-630 augments radioresistance by inducing an anti-apoptotic effect via the Nrf2–GPX2 molecular axis in HNC. The modulation of miR-630 may serve as a novel radiosensitizing target for HNC. Full article
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32 pages, 17861 KiB  
Article
Antifibrotic Effect of Selenium-Containing Nanoparticles on a Model of TAA-Induced Liver Fibrosis
by Elena G. Varlamova, Michail Victorovich Goltyaev, Vladimir Vladimirovich Rogachev, Sergey V. Gudkov, Elena V. Karaduleva and Egor A. Turovsky
Cells 2023, 12(23), 2723; https://doi.org/10.3390/cells12232723 - 28 Nov 2023
Viewed by 1264
Abstract
For the first time, based on the expression analysis of a wide range of pro- and anti-fibrotic, pro- and anti-inflammatory, and pro- and anti-apoptotic genes, key markers of endoplasmic reticulum stress (ER-stress), molecular mechanisms for the regulation of fibrosis, and accompanying negative processes [...] Read more.
For the first time, based on the expression analysis of a wide range of pro- and anti-fibrotic, pro- and anti-inflammatory, and pro- and anti-apoptotic genes, key markers of endoplasmic reticulum stress (ER-stress), molecular mechanisms for the regulation of fibrosis, and accompanying negative processes caused by thioacetamide (TAA) injections and subsequent injections of selenium-containing nanoparticles and sorafenib have been proposed. We found that selenium nanoparticles of two types (doped with and without sorafenib) led to a significant decrease in almost all pro-fibrotic and pro-inflammatory genes. Sorafenib injections also reduced mRNA expression of pro-fibrotic and pro-inflammatory genes but less effectively than both types of nanoparticles. In addition, it was shown for the first time that TAA can be an inducer of ER-stress, most likely activating the IRE1α and PERK signaling pathways of the UPR, an inducer of apoptosis and pyroptosis. Sorafenib, despite a pronounced anti-apoptotic effect, still did not reduce the expression of caspase-3 and 12 or mitogen-activated kinase JNK1 to control values, which increases the risk of persistent apoptosis in liver cells. After injections of selenium-containing nanoparticles, the negative effects caused by TAA were leveled, causing an adaptive UPR signaling response through activation of the PERK signaling pathway. The advantages of selenium-containing nanoparticles over sorafenib, established in this work, once again emphasize the unique properties of this microelement and serve as an important factor for the further introduction of drugs based on it into clinical practice. Full article
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13 pages, 2842 KiB  
Article
FKBP38 Regulates Self-Renewal and Survival of GBM Neurospheres
by Aimee L. Dowling, Stuart Walbridge, Celine Ertekin, Sriya Namagiri, Krystal Camacho, Ashis Chowdhury, Jean-Paul Bryant, Eric Kohut, John D. Heiss, Desmond A. Brown, Sangamesh G. Kumbar and Yeshavanth Kumar Banasavadi-Siddegowda
Cells 2023, 12(21), 2562; https://doi.org/10.3390/cells12212562 - 2 Nov 2023
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Abstract
Glioblastoma is the most common malignant primary brain tumor. The outcome is dismal, despite the multimodal therapeutic approach that includes surgical resection, followed by radiation and chemotherapy. The quest for novel therapeutic targets to treat glioblastoma is underway. FKBP38, a member of the [...] Read more.
Glioblastoma is the most common malignant primary brain tumor. The outcome is dismal, despite the multimodal therapeutic approach that includes surgical resection, followed by radiation and chemotherapy. The quest for novel therapeutic targets to treat glioblastoma is underway. FKBP38, a member of the immunophilin family of proteins, is a multidomain protein that plays an important role in the regulation of cellular functions, including apoptosis and autophagy. In this study, we tested the role of FKBP38 in glioblastoma tumor biology. Expression of FKBP38 was upregulated in the patient-derived primary glioblastoma neurospheres (GBMNS), compared to normal human astrocytes. Attenuation of FKBP38 expression decreased the viability of GBMNSs and increased the caspase 3/7 activity, indicating that FKBP38 is required for the survival of GBMNSs. Further, the depletion of FKBP38 significantly reduced the number of neurospheres that were formed, implying that FKBP38 regulates the self-renewal of GBMNSs. Additionally, the transient knockdown of FKBP38 increased the LC3-II/I ratio, suggesting the induction of autophagy with the depletion of FKBP38. Further investigation showed that the negative regulation of autophagy by FKBP38 in GBMNSs is mediated through the JNK/C-Jun–PTEN–AKT pathway. In vivo, FKBP38 depletion significantly extended the survival of tumor-bearing mice. Overall, our results suggest that targeting FKBP38 imparts an anti-glioblastoma effect by inducing apoptosis and autophagy and thus can be a potential therapeutic target for glioblastoma therapy. Full article
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15 pages, 3266 KiB  
Article
DPP8 Selective Inhibitor Tominostat as a Novel and Broad-Spectrum Anticancer Agent against Hematological Malignancies
by Shohei Kikuchi, Akinori Wada, Yusuke Kamihara, Kosuke Okazaki, Paras Jawaid, Mati Ur Rehman, Eiji Kobayashi, Takeshi Susukida, Tomoki Minemura, Yoshimi Nabe, Noriaki Iwao, Tatsuhiko Ozawa, Ryo Hatano, Mitsugu Yamada, Hiroyuki Kishi, Yuji Matsuya, Mineyuki Mizuguchi, Yoshihiro Hayakawa, Nam H. Dang, Yasumitsu Sakamoto, Chikao Morimoto and Tsutomu Satoadd Show full author list remove Hide full author list
Cells 2023, 12(7), 1100; https://doi.org/10.3390/cells12071100 - 6 Apr 2023
Viewed by 2465
Abstract
DPP8/9 inhibition induces either pyroptotic or apoptotic cell death in hematological malignancies. We previously reported that treatment with the DPP8/9 inhibitor 1G244 resulted in apoptotic cell death in myeloma, and our current study further evaluates the mechanism of action of 1G244 in different [...] Read more.
DPP8/9 inhibition induces either pyroptotic or apoptotic cell death in hematological malignancies. We previously reported that treatment with the DPP8/9 inhibitor 1G244 resulted in apoptotic cell death in myeloma, and our current study further evaluates the mechanism of action of 1G244 in different blood cancer cell lines. Specifically, 1G244 inhibited DPP9 to induce GSDMD-mediated-pyroptosis at low concentrations and inhibited DPP8 to cause caspase-3-mediated-apoptosis at high concentrations. HCK expression is necessary to induce susceptibility to pyroptosis but does not participate in the induction of apoptosis. To further characterize this DPP8-dependent broad-spectrum apoptosis induction effect, we evaluated the potential antineoplastic role for an analog of 1G244 with higher DPP8 selectivity, tominostat (also known as 12 m). In vitro studies demonstrated that the cytotoxic effect of 1G244 at high concentrations was enhanced in tominostat. Meanwhile, in vivo work showed tominostat exhibited antitumor activity that was more effective on a cell line sensitive to 1G244, and at higher doses, it was also effective on a cell line resistant to 1G244. Importantly, the weight loss morbidity associated with increasing doses of 1G244 was not observed with tominostat. These results suggest the possible development of novel drugs with antineoplastic activity against selected hematological malignancies by refining and increasing the DPP8 selectivity of tominostat. Full article
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Review

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34 pages, 1139 KiB  
Review
Cell Death, by Any Other Name…
by Mustapha Kandouz
Cells 2024, 13(4), 325; https://doi.org/10.3390/cells13040325 - 10 Feb 2024
Viewed by 1284
Abstract
Studies trying to understand cell death, this ultimate biological process, can be traced back to a century ago. Yet, unlike many other fashionable research interests, research on cell death is more alive than ever. New modes of cell death are discovered in specific [...] Read more.
Studies trying to understand cell death, this ultimate biological process, can be traced back to a century ago. Yet, unlike many other fashionable research interests, research on cell death is more alive than ever. New modes of cell death are discovered in specific contexts, as are new molecular pathways. But what is “cell death”, really? This question has not found a definitive answer yet. Nevertheless, part of the answer is irreversibility, whereby cells can no longer recover from stress or injury. Here, we identify the most distinctive features of different modes of cell death, focusing on the executive final stages. In addition to the final stages, these modes can differ in their triggering stimulus, thus referring to the initial stages. Within this framework, we use a few illustrative examples to examine how intercellular communication factors in the demise of cells. First, we discuss the interplay between cell–cell communication and cell death during a few steps in the early development of multicellular organisms. Next, we will discuss this interplay in a fully developed and functional tissue, the gut, which is among the most rapidly renewing tissues in the body and, therefore, makes extensive use of cell death. Furthermore, we will discuss how the balance between cell death and communication is modified during a pathological condition, i.e., colon tumorigenesis, and how it could shed light on resistance to cancer therapy. Finally, we briefly review data on the role of cell–cell communication modes in the propagation of cell death signals and how this has been considered as a potential therapeutic approach. Far from vainly trying to provide a comprehensive review, we launch an invitation to ponder over the significance of cell death diversity and how it provides multiple opportunities for the contribution of various modes of intercellular communication. Full article
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