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Cells
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DNA Damage and Senescence in Cellular Response to Cancer Therapies
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DNA Damage and Senescence in Cellular Response to Cancer Therapies

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

Deadline for manuscript submissions: closed (15 April 2023) | Viewed by 11864

Special Issue Editors

Dr. Manuela Pellegrini

E-Mail Website
Guest Editor
Institute of Biochemistry and Cell Biology, IBBC-CNR, via E. Ramarini, 32, 00015 Monterotondo Scalo, Rome, Italy
Interests: atm; mouse models; A-T; DNA damage; senescence; signaling cascade; genomic stability; lymphoma
Special Issues, Collections and Topics in MDPI journals
Dr. Maria Laura Falchetti

E-Mail Website
Guest Editor
Institute of Biochemistry and Cell Biology, IBBC-CNR, via E. Ramarini, 32, 00015 Monterotondo Scalo, Rome, Italy
Interests: cell senescence; cancer therapy
Dr. Maria Patrizia Mongiardi

E-Mail Website
Guest Editor
Institute of Biochemistry and Cell Biology, IBBC-CNR, via E. Ramarini, 32, 00015 Monterotondo Scalo, Rome, Italy
Interests: senescence
Dr. Andrea Levi

E-Mail Website
Guest Editor
Institute of Biochemistry and Cell Biology, IBBC-CNR, via E. Ramarini, 32, 00015 Monterotondo Scalo, Rome, Italy
Interests: DNA damage

Special Issue Information

Dear Colleagues,

Chemotherapy and radiotherapy act by inducing DNA damage and the activation of the DNA damage response (DDR) during cancer treatment. This crucial cellular response triggers a series of events that may eventually result in cell death or, alternatively, in DNA repair and cell survival. The persistence of DNA damage may allow for a permanent cell cycle arrest and the establishment of cell senescence. A senescent cell is a metabolically active cell that does not proliferate, shows peculiar histone modifications, and communicates with its microenvironment through a Senescent Associate Secretory Phenotype (SASP), a secretome that is rich in cytokines and chemokines. Both therapy-induced DNA damage and the senescent phenotype are a Janus-like events: on one hand, they might limit tumor expansion, but DNA damage may activate the aberrant genomic recombination, and the SASP of senescent cancer and stromal cells in the tumor microenvironment may induce the release of paracrine molecules, ultimately promoting the growth of more aggressive cancer subclones.

In this Special Issue, we hope to collect observations and discussions on the role of DNA damage and senescence in different types of tumors; the role of tumor and non-tumor senescent cells on cancer progression; the role of DNA damage and senescence on the immune system and in immunotherapies; the molecular aspects of cell response to therapies involving DNA damage machinery and senescence; and the impact of therapy-induced DNA damage and senescence on tumor aggressiveness and therapy resistance.

Dr. Manuela Pellegrini
Dr. Maria Laura Falchetti
Dr. Maria Patrizia Mongiardi
Dr. Andrea Levi
Guest Editors

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. Cells 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 2700 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.

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Published Papers (4 papers)

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Research

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26 pages, 4086 KiB  
Article
MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER+ Breast Cancer
by Janine Wörthmüller, Simona Disler, Sylvain Pradervand, François Richard, Lisa Haerri, Gustavo A. Ruiz Buendía, Nadine Fournier, Christine Desmedt and Curzio Rüegg
Cells 2023, 12(15), 1929; https://doi.org/10.3390/cells12151929 - 25 Jul 2023
Cited by 1 | Viewed by 2339
Abstract
MAGI1 acts as a tumor suppressor in estrogen receptor-positive (ER+) breast cancer (BC), and its loss correlates with a more aggressive phenotype. To identify the pathways and events affected by MAGI1 loss, we deleted the MAGI1 gene in the ER+ [...] Read more.
MAGI1 acts as a tumor suppressor in estrogen receptor-positive (ER+) breast cancer (BC), and its loss correlates with a more aggressive phenotype. To identify the pathways and events affected by MAGI1 loss, we deleted the MAGI1 gene in the ER+ MCF7 BC cell line and performed RNA sequencing and functional experiments in vitro. Transcriptome analyses revealed gene sets and biological processes related to estrogen signaling, the cell cycle, and DNA damage responses affected by MAGI1 loss. Upon exposure to TNF-α/IFN-γ, MCF7 MAGI1 KO cells entered a deeper level of quiescence/senescence compared with MCF7 control cells and activated the AKT and MAPK signaling pathways. MCF7 MAGI1 KO cells exposed to ionizing radiations or cisplatin had reduced expression of DNA repair proteins and showed increased sensitivity towards PARP1 inhibition using olaparib. Treatment with PI3K and AKT inhibitors (alpelisib and MK-2206) restored the expression of DNA repair proteins and sensitized cells to fulvestrant. An analysis of human BC patients’ transcriptomic data revealed that patients with low MAGI1 levels had a higher tumor mutational burden and homologous recombination deficiency. Moreover, MAGI1 expression levels negatively correlated with PI3K/AKT and MAPK signaling, which confirmed our in vitro observations. Pharmacological and genomic evidence indicate HDACs as regulators of MAGI1 expression. Our findings provide a new view on MAGI1 function in cancer and identify potential treatment options to improve the management of ER+ BC patients with low MAGI1 levels. Full article
(This article belongs to the Special Issue DNA Damage and Senescence in Cellular Response to Cancer Therapies)
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19 pages, 5600 KiB  
Article
Residual Foci of DNA Damage Response Proteins in Relation to Cellular Senescence and Autophagy in X-Ray Irradiated Fibroblasts
by Andrey Osipov, Anna Chigasova, Elizaveta Yashkina, Maxim Ignatov, Yuriy Fedotov, Daria Molodtsova, Natalia Vorobyeva and Andreyan N. Osipov
Cells 2023, 12(8), 1209; https://doi.org/10.3390/cells12081209 - 21 Apr 2023
Cited by 7 | Viewed by 1988
Abstract
DNA repair (DNA damage) foci observed 24 h and later after irradiation are called “residual” in the literature. They are believed to be the repair sites for complex, potentially lethal DNA double strand breaks. However, the features of their post-radiation dose-dependent quantitative changes [...] Read more.
DNA repair (DNA damage) foci observed 24 h and later after irradiation are called “residual” in the literature. They are believed to be the repair sites for complex, potentially lethal DNA double strand breaks. However, the features of their post-radiation dose-dependent quantitative changes and their role in the processes of cell death and senescence are still insufficiently studied. For the first time in one work, a simultaneous study of the association of changes in the number of residual foci of key DNA damage response (DDR) proteins (γH2AX, pATM, 53BP1, p-p53), the proportion of caspase-3 positive, LC-3 II autophagic and SA-β-gal senescent cells was carried out 24–72 h after fibroblast irradiation with X-rays at doses of 1–10 Gy. It was shown that with an increase in time after irradiation from 24 h to 72 h, the number of residual foci and the proportion of caspase-3 positive cells decrease, while the proportion of senescent cells, on the contrary, increases. The highest number of autophagic cells was noted 48 h after irradiation. In general, the results obtained provide important information for understanding the dynamics of the development of a dose-dependent cellular response in populations of irradiated fibroblasts. Full article
(This article belongs to the Special Issue DNA Damage and Senescence in Cellular Response to Cancer Therapies)
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18 pages, 3900 KiB  
Article
EA.hy926 Cells and HUVECs Share Similar Senescence Phenotypes but Respond Differently to the Senolytic Drug ABT-263
by Ibrahim Y. Abdelgawad, Kevin Agostinucci, Somia G. Ismail, Marianne K. O. Grant and Beshay N. Zordoky
Cells 2022, 11(13), 1992; https://doi.org/10.3390/cells11131992 - 21 Jun 2022
Cited by 10 | Viewed by 4293
Abstract
Doxorubicin (DOX) induces endothelial cell (EC) senescence, which contributes to endothelial dysfunction and cardiovascular complications. Senolytic drugs selectively eliminate senescent cells to ameliorate senescence-mediated pathologies. Previous studies have demonstrated differences between immortalized and primary EC models in some characteristics. However, the response of [...] Read more.
Doxorubicin (DOX) induces endothelial cell (EC) senescence, which contributes to endothelial dysfunction and cardiovascular complications. Senolytic drugs selectively eliminate senescent cells to ameliorate senescence-mediated pathologies. Previous studies have demonstrated differences between immortalized and primary EC models in some characteristics. However, the response of DOX-induced senescent ECs to senolytics has not been determined across these two models. In the present work, we first established a comparative characterization of DOX-induced senescence phenotypes in immortalized EA.hy926 endothelial-derived cells and primary human umbilical vein EC (HUVECs). Thereafter, we evaluated the senolytic activity of four senolytics across both ECs. Following the DOX treatment, both EA.hy926 and HUVECs shared similar senescence phenotypes characterized by upregulated senescence markers, increased SA-β-gal activity, cell cycle arrest, and elevated expression of the senescence-associated secretory phenotype (SASP). The potentially senolytic drugs dasatinib, quercetin, and fisetin demonstrated a lack of selectivity against DOX-induced senescent EA.hy926 cells and HUVECs. However, ABT-263 (Navitoclax) selectively induced the apoptosis of DOX-induced senescent HUVECs but not EA.hy926 cells. Mechanistically, DOX-treated EA.hy926 cells and HUVECs demonstrated differential expression levels of the BCL-2 family proteins. In conclusion, both EA.hy926 cells and HUVECs demonstrate similar DOX-induced senescence phenotypes but they respond differently to ABT-263, presumably due to the different expression levels of BCL-2 family proteins. Full article
(This article belongs to the Special Issue DNA Damage and Senescence in Cellular Response to Cancer Therapies)
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Review

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20 pages, 406 KiB  
Review
Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications
by Damian Jaworski, Bartosz Brzoszczyk and Łukasz Szylberg
Cells 2023, 12(10), 1375; https://doi.org/10.3390/cells12101375 - 12 May 2023
Cited by 1 | Viewed by 2345
Abstract
Prostate cancer remains a leading cause of cancer-related death in men worldwide. Recent research advances have emphasized the critical roles of mismatch repair (MMR) and double-strand break (DSB) in prostate cancer development and progression. Here, we provide a comprehensive review of the molecular [...] Read more.
Prostate cancer remains a leading cause of cancer-related death in men worldwide. Recent research advances have emphasized the critical roles of mismatch repair (MMR) and double-strand break (DSB) in prostate cancer development and progression. Here, we provide a comprehensive review of the molecular mechanisms underlying DSB and MMR defects in prostate cancer, as well as their clinical implications. Furthermore, we discuss the promising therapeutic potential of immune checkpoint inhibitors and PARP inhibitors in targeting these defects, particularly in the context of personalized medicine and further perspectives. Recent clinical trials have demonstrated the efficacy of these novel treatments, including Food and Drugs Association (FDA) drug approvals, offering hope for improved patient outcomes. Overall, this review emphasizes the importance of understanding the interplay between MMR and DSB defects in prostate cancer to develop innovative and effective therapeutic strategies for patients. Full article
(This article belongs to the Special Issue DNA Damage and Senescence in Cellular Response to Cancer Therapies)
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