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Cancers
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Harnessing Cancer Vulnerability by Targeting the DNA Damage Response
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Harnessing Cancer Vulnerability by Targeting the DNA Damage Response

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 14665

Special Issue Editor

Dr. Angela Celetti

E-Mail Website
Guest Editor
Departement of Biomedical Science, Institute for Experimental Oncology and Endocrinology, National Research Council (CNR, ITALY), Via Pansini, 5, 80131, Naples, Italy
Interests: cancer stem cells and drug resistance; targeting ddr defects

Special Issue Information

Dear Colleagues,

In the precision medicine era, while agents that suppress oncogenic kinases have changed the standard of care for many cancers, no effective therapies are available for tumours, such as breast and ovarian cancer (OC), which are lacking in actionable driver cancer mutations. Luckily, the genome instability induced by the high frequency of DNA damage repair (DDR) defects has opened new avenues and treatment perspectives for such tumours. As a matter of fact, the enzymatic inhibition of the Poly(ADP-ribose) polymerases (PARPs) 1 and 2 has pioneered a synthetic lethality-based target therapy strategy for treatment of tumours characterised by DDR defects, for instance, breast and ovarian cancer carrying BRCA1 and BRCA2 mutations.

My main interest in launching this Special Issue is to focus the discussion on innovative data in order to support clinical strategies for extending the advantages of PARP inhibitors beyond BRCA mutant cancers and towards a wider number of patients, through the use of novel biomarkers of homologous recombination repair deficiency as well as of predictive biomarkers of sensitivity. I would like to attract research and/or review articles to explore the potential application of PARP inhibitors in early treatment schemes, including neoadjuvant, adjuvant, and chemo/radio-prevention approaches. In fact, it is my firm conviction that the challenge of combinatorial therapeutic strategies, including different DDR inhibitor, immune-checkpoint inhibitors, and/or non-DDR agents, able to induce chemical BRCAness, must be pursued and encouraged.

Dr. Angela Celetti
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.

Keywords

  • tumor suppressor
  • DNA damage repair
  • homologous recombination
  • synthetic lethality
  • BRCAness
  • drug-resistant cancer cells
  • targeted therapy
  • PARP-inhibitors
  • lung cancers
  • urothelial and prostate cancer
  • ovarian cancer

Published Papers (5 papers)

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Research

18 pages, 2895 KiB  
Article
Enhanced Cytotoxicity on Cancer Cells by Combinational Treatment of PARP Inhibitor and 5-Azadeoxycytidine Accompanying Distinct Transcriptional Profiles
by Tomonori Araki, Kensuke Hamada, Aung Bhone Myat, Hideki Ogino, Kohei Hayashi, Miho Maeda, Ying Tong, Yasufumi Murakami, Kazuhiko Nakao and Mitsuko Masutani
Cancers 2022, 14(17), 4171; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14174171 - 28 Aug 2022
Viewed by 1419
Abstract
Poly(ADP-ribose) polymerase (PARP) is involved in DNA repair and chromatin regulation. 5-Aza-2′-deoxycytidine (5-aza-dC) inhibits DNA methyltransferases, induces hypomethylation, blocks DNA replication, and causes DNA single strand breaks (SSBs). As the PARP inhibitor is expected to affect both DNA repair and transcriptional regulations, we [...] Read more.
Poly(ADP-ribose) polymerase (PARP) is involved in DNA repair and chromatin regulation. 5-Aza-2′-deoxycytidine (5-aza-dC) inhibits DNA methyltransferases, induces hypomethylation, blocks DNA replication, and causes DNA single strand breaks (SSBs). As the PARP inhibitor is expected to affect both DNA repair and transcriptional regulations, we investigated the effect of combinational use of PARP inhibitors on cytotoxicity of 5-aza-dC in human cancer cell lines. The combinational treatment of 5-aza-dC and PARP inhibitor PJ-34 exhibited a stronger cytotoxicity compared with their treatment alone in blood cancer HL-60, U937, and colon cancer HCT116 and RKO cells. Treatment with 5-aza-dC but not PJ-34 caused SSBs in HCT116 cell lines. Global genome DNA demethylation was observed after treatment with 5-aza-dC but not with PJ-34. Notably, in microarray analysis, combinational treatment with PJ-34 and 5-aza-dC caused dissimilar broad changes in gene expression profiles compared with their single treatments in both HCT116 and RKO cells. The profiles of reactivation of silenced genes were also different in combination of PJ-34 and 5-aza-dC and their single treatments. The results suggest that the combinational use of 5-aza-dC and PARP inhibitor may be useful by causing distinct transcriptional profile changes. Full article
(This article belongs to the Special Issue Harnessing Cancer Vulnerability by Targeting the DNA Damage Response)
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15 pages, 23206 KiB  
Article
Neuropilin-1 Expression Associates with Poor Prognosis in HNSCC and Elicits EGFR Activation upon CDDP-Induced Cytotoxic Stress
by Virginia Napolitano, Daniela Russo, Francesco Morra, Francesco Merolla, Silvia Varricchio, Gennaro Ilardi, Rosa Maria Di Crescenzo, Francesco Martino, Massimo Mascolo, Angela Celetti, Luca Tamagnone and Stefania Staibano
Cancers 2021, 13(15), 3822; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153822 - 29 Jul 2021
Cited by 3 | Viewed by 1900
Abstract
Head and neck squamous cell carcinoma (HNSCC) includes a group of aggressive malignancies characterized by the overexpression of the epidermal growth factor receptor (EGFR) in 90% of cases. Neuropilin-1 (NRP-1) acts as an EGFR co-receptor, enhancing, upon ligand stimulation, EGFR signaling in several [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) includes a group of aggressive malignancies characterized by the overexpression of the epidermal growth factor receptor (EGFR) in 90% of cases. Neuropilin-1 (NRP-1) acts as an EGFR co-receptor, enhancing, upon ligand stimulation, EGFR signaling in several cellular models. However, NRP-1 remains poorly characterized in HNSCC. By utilizing in vitro cellular models of HNSCC, we report that NRP-1 is involved in the regulation of EGFR signaling. In fact, NRP-1 can lead to cisplatin-induced EGFR phosphorylation, an escape mechanism activated by cancer cells upon cytotoxic stress. Furthermore, we evaluated Neuropilin-1 staining in tissue samples of an HNSCC case series (n = 218), unraveling a prognostic value for the Neuropilin-1 tissue expression. These data suggest a potential role for NRP-1 in HNSCC cancer progression, expanding the repertoire of signaling in which NRP-1 is involved and eliciting the need for further investigations on NRP-1 as a suitable target for HNSCC novel therapeutic approaches. Full article
(This article belongs to the Special Issue Harnessing Cancer Vulnerability by Targeting the DNA Damage Response)
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22 pages, 4478 KiB  
Article
PFKFB3 Inhibition Sensitizes DNA Crosslinking Chemotherapies by Suppressing Fanconi Anemia Repair
by Anna Huguet Ninou, Jemina Lehto, Dimitrios Chioureas, Hannah Stigsdotter, Korbinian Schelzig, Emma Åkerlund, Greta Gudoityte, Ulrika Joneborg, Joseph Carlson, Jos Jonkers, Brinton Seashore-Ludlow and Nina Marie Susanne Gustafsson
Cancers 2021, 13(14), 3604; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143604 - 18 Jul 2021
Cited by 6 | Viewed by 3987
Abstract
Replicative repair of interstrand crosslinks (ICL) generated by platinum chemotherapeutics is orchestrated by the Fanconi anemia (FA) repair pathway to ensure resolution of stalled replication forks and the maintenance of genomic integrity. Here, we identify novel regulation of FA repair by the cancer-associated [...] Read more.
Replicative repair of interstrand crosslinks (ICL) generated by platinum chemotherapeutics is orchestrated by the Fanconi anemia (FA) repair pathway to ensure resolution of stalled replication forks and the maintenance of genomic integrity. Here, we identify novel regulation of FA repair by the cancer-associated glycolytic enzyme PFKFB3 that has functional consequences for replication-associated ICL repair and cancer cell survival. Inhibition of PFKFB3 displays a cancer-specific synergy with platinum compounds in blocking cell viability and restores sensitivity in treatment-resistant models. Notably, the synergies are associated with DNA-damage-induced chromatin association of PFKFB3 upon cancer transformation, which further increases upon platinum resistance. FA pathway activation triggers the PFKFB3 assembly into nuclear foci in an ATR- and FANCM-dependent manner. Blocking PFKFB3 activity disrupts the assembly of key FA repair factors and consequently prevents fork restart. This results in an incapacity to replicate cells to progress through S-phase, an accumulation of DNA damage in replicating cells, and fork collapse. We further validate PFKFB3-dependent regulation of FA repair in ex vivo cultures from cancer patients. Collectively, targeting PFKFB3 opens up therapeutic possibilities to improve the efficacy of ICL-inducing cancer treatments. Full article
(This article belongs to the Special Issue Harnessing Cancer Vulnerability by Targeting the DNA Damage Response)
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20 pages, 5643 KiB  
Article
Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis
by Ming-Yao Chen, Vijesh Kumar Yadav, Yi Cheng Chu, Jiann Ruey Ong, Ting-Yi Huang, Kwai-Fong Lee, Kuen-Haur Lee, Chi-Tai Yeh and Wei-Hwa Lee
Cancers 2021, 13(13), 3227; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133227 - 28 Jun 2021
Cited by 25 | Viewed by 2986 | Correction
Abstract
Sorafenib is used for treating advanced hepatocellular carcinoma (HCC), but some patients acquire sorafenib resistance. We investigated the mechanisms underlying acquired sorafenib resistance in HCC cells and targeted them to re-sensitize them to sorafenib. In silico analysis indicated that toll-like receptor (TLR)-9 was [...] Read more.
Sorafenib is used for treating advanced hepatocellular carcinoma (HCC), but some patients acquire sorafenib resistance. We investigated the mechanisms underlying acquired sorafenib resistance in HCC cells and targeted them to re-sensitize them to sorafenib. In silico analysis indicated that toll-like receptor (TLR)-9 was significantly overexpressed, and that miRNA (hsa-miR-30a-5p) was downregulated in sorafenib-resistant HCC cells, which modulated HCC cell proliferation, oxidative stress, and apoptosis. TLR9 overexpression increased HCC cell proliferation, whereas TLR9 inhibition from hydroxychloroquine (HCQ) decreased HCC cell proliferation, tumor growth, oxidative stress marker (SOD1), and the formation of autophagosome bodies (reduced ATG5 and Beclin-1 expression). Moreover, HCQ treatment reduced epithelial–mesenchymal transition, leading to decreased clonogenicity, migratory ability, and invasiveness. HCQ targeted and reduced the self-renewal capacity phenotype by inhibiting tumorsphere generation. Both in vitro and in vivo results demonstrated the synergistic effect of the HCQ–sorafenib combination on sorafenib-resistant HCC (Huh7-SR) cells, increasing their sensitivity to treatment by modulating TLR9, autophagy (ATG5 and Beclin-1), oxidative stress (SOD1), and apoptosis (c-caspase3) expression and thus overcoming the drug resistance. This study’s findings indicate that TLR9 overexpression occurs in sorafenib-resistant HCC cells and that its downregulation aids HCC suppression. Moreover, HCQ treatment significantly increases sorafenib’s effect on sorafenib-resistant HCC cells. Full article
(This article belongs to the Special Issue Harnessing Cancer Vulnerability by Targeting the DNA Damage Response)
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22 pages, 7588 KiB  
Article
Induced Mitochondrial Alteration and DNA Damage via IFNGR-JAK2-STAT1-PARP1 Pathway Facilitates Viral Hepatitis Associated Hepatocellular Carcinoma Aggressiveness and Stemness
by Yih-Giun Cherng, Yi Cheng Chu, Vijesh Kumar Yadav, Ting-Yi Huang, Ming-Shou Hsieh, Kwai-Fong Lee, Wei-Hwa Lee, Chi-Tai Yeh and Jiann Ruey Ong
Cancers 2021, 13(11), 2755; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112755 - 02 Jun 2021
Cited by 11 | Viewed by 3459
Abstract
Background: Hepatitis virus is a major risk factor for liver cancer. The mitochondrial dysfunction IFN gamma-related pathways are activated after virus infection. Jak family-related protein is involved in the downstream of IFN gamma-related pathways. However, the effect of the IFNGR-JAK-STAT pathway acting as [...] Read more.
Background: Hepatitis virus is a major risk factor for liver cancer. The mitochondrial dysfunction IFN gamma-related pathways are activated after virus infection. Jak family-related protein is involved in the downstream of IFN gamma-related pathways. However, the effect of the IFNGR-JAK-STAT pathway acting as functional regulators of their related protein expression on virus infection and hepatocellular carcinoma (HCC) remains unclear. Interestingly, the role of the DNA repair gene (PARP1) in therapy resistant cancers also has not been studied and explored well. In this study, we hypothesized that momelotinib could suppress the progression of HCC by targeting Jak family related and PARP1 DNA repair protein. Based on this observation, we link the relevant targets of the JAK family and the potential applications of targeted therapy inhibitors. Methods: We analyzed possible synergism between momelotinib and sorafenib in hepatitis virus-associated liver cancer. Immunostaining, colony formation assay, cell invasion, migration, and tumorsphere-formation assay were used for drug cytotoxicity, cell viability, and possible molecular mechanism. Result: We first demonstrated that the expression of Jak1 and 2 is significantly upregulated in vHCC than in nvHCC/normal liver tissues. In addition, the gene expression of IFN gamma-related pathways is activated after virus infection. Additionally, we found that momelotinib significantly inhibited the growth of HCC cells and reduces the expression of Jak2, which showed the importance of momelotinib in targeting Jak2 and reducing tumorigenesis in HCC. Meanwhile, momelotinib effectively inhibited the IFNGR-JAK-STAT pathway and reduced the migratory/invasive ability of vHCC cells through down-regulating EMT biomarkers (E-cadherin and vimentin), transcription factor (Slug), and significantly inhibits the DNA damage repair enzyme PARP1. It also induced cell apoptosis of vHCC cells. Furthermore, the combined effect of momelotinib and sorafenib both at in vitro and in vivo synergistically suppresses the proliferation of vHCC cells and effectively reduces the tumor burden. Conclusions: Our results showed that momelotinib effectively suppressed the expression of the IFNGR-JAK-STAT-PARP1 pathway, which results in the downregulation of cancer stem cell genes and enhances the antitumor efficacy of sorafenib by initiating the expression of apoptosis-related genes and inhibiting the DNA repair gene in vHCC cells, thus maximizing its therapeutic potential for patients with HCC. Full article
(This article belongs to the Special Issue Harnessing Cancer Vulnerability by Targeting the DNA Damage Response)
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