scholarly journals Downregulation of DNMT3a expression increases miR-182-induced apoptosis of ovarian cancer through caspase-3 and caspase-9-mediated apoptosis and DNA damage response

2016 ◽  
Vol 36 (6) ◽  
pp. 3597-3604 ◽  
Author(s):  
Wei Lu ◽  
Tanmin Lu ◽  
Xin Wei
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Caspase 3 ◽  
Caspase 9 ◽  
Damage Response ◽  
Induced Apoptosis

scholarly journals The role of ROS and subsequent DNA-damage response in PUMA-induced apoptosis of ovarian cancer cells

Oncotarget ◽  
2017 ◽  
Vol 8 (14) ◽  
pp. 23492-23506 ◽  
Author(s):  
Jun Yang ◽  
Xinyu Zhao ◽  
Mei Tang ◽  
Lei Li ◽  
Yi Lei ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Ovarian Cancer Cells ◽  
Damage Response ◽  
Induced Apoptosis

scholarly journals ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. VOLUME 283 (2008) PAGES 6572-6583

2008 ◽  
Vol 283 (22) ◽  
pp. 15512
Author(s):  
Navjotsingh Pabla ◽  
Shuang Huang ◽  
Qing-Sheng Mi ◽  
Rene Daniel ◽  
Zheng Dong
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Damage Response ◽  
P53 Activation ◽  
Induced Apoptosis

scholarly journals Genomic, Transcriptomic, and Functional Alterations in DNA Damage Response Pathways as Putative Biomarkers of Chemotherapy Response in Ovarian Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1420
Author(s):  
Sweta Sharma Saha ◽  
Lucy Gentles ◽  
Alice Bradbury ◽  
Dominik Brecht ◽  
Rebecca Robinson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Personalised Medicine ◽  
Primary Cultures ◽  
The Cancer Genome Atlas ◽  
Chemotherapy Response ◽  
Chemotherapy Drugs ◽  
Ovarian Cancers ◽  
Damage Response

Defective DNA damage response (DDR) pathways are enabling characteristics of cancers that not only can be exploited to specifically target cancer cells but also can predict chemotherapy response. Defective Homologous Recombination Repair (HRR) function, e.g., due to BRCA1/2 loss, is a determinant of response to platinum agents and PARP inhibitors in ovarian cancers. Most chemotherapies function by either inducing DNA damage or impacting on its repair but are generally used in the clinic unselectively. The significance of HRR and other DDR pathways in determining response to several other chemotherapy drugs is not well understood. In this study, the genomic, transcriptomic and functional analysis of DDR pathways in a panel of 14 ovarian cancer cell lines identified that defects in DDR pathways could determine response to several chemotherapy drugs. Carboplatin, rucaparib, and topotecan sensitivity were associated with functional loss of HRR (validated in 10 patient-derived primary cultures) and mismatch repair. Two DDR gene expression clusters correlating with treatment response were identified, with PARP10 identified as a novel marker of platinum response, which was confirmed in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Reduced non-homologous end-joining function correlated with increased sensitivity to doxorubicin, while cells with high intrinsic oxidative stress showed sensitivity to gemcitabine. In this era of personalised medicine, molecular/functional characterisation of DDR pathways could guide chemotherapy choices in the clinic allowing specific targeting of ovarian cancers.

scholarly journals 900 Depleting non-canonical, cell-intrinsic PD-L1 signals induces synthetic lethality to small molecule DNA damage response inhibitors in an immune independent and dependent manner

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A944-A944
Author(s):  
Anand Kornepati ◽  
Clare Murray ◽  
Barbara Avalos ◽  
Cody Rogers ◽  
Kavya Ramkumar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Small Molecule ◽  
Treatment Resistance ◽  
Programmed Death ◽  
Damage Response ◽  
Response Biomarker

BackgroundTumor surface-expressed programmed death-ligand 1 (PD-L1) suppresses immunity when it engages programmed death-1 (PD-1) on anti-tumor immune cells in canonical PD-L1/PD-1.1 Non-canonical, tumour-intrinsic PD-L1 signals can mediate treatment resistance2–6 but mechanisms remain incompletely understood. Targeting non-canonical, cell-intrinsic PD-L1 signals, especially modulation of the DNA damage response (DDR), remains largely untapped.MethodsWe made PD-L1 knockout (PD-L1 KO) murine transplantable and human cell lines representing melanoma, bladder, and breast histologies. We used biochemical, genetic, and cell-biology techniques for mechanistic insights into tumor-intrinsic PD-L1 control of specific DDR and DNA repair pathways. We generated a novel inducible melanoma GEMM lacking PD-L1 only in melanocytes to corroborate DDR alterations observed in PD-L1 KO of established tumors.ResultsGenetic tumor PD-L1 depletion destabilized Chk2 and impaired ATM/Chk2, but not ATR/Chk1 DDR. PD-L1KO increased DNA damage (γH2AX) and impaired homologous recombination DNA repair (p-RPA32, BRCA1, RAD51 nuclear foci) and function (DR-GFP reporter). PD-L1 KO cells were significantly more sensitive versus controls to DDR inhibitors (DDRi) against ATR, Chk1, and PARP but not ATM in multiple human and mouse tumor models in vitro and in vivo in NSG mice. PD-1 independent, intracellular, not surface PD-L1 stabilized Chk2 protein with minimal Chek2 mRNA effect. Mechanistically, PD-L1 could directly complex with Chk2, protecting it from PIRH2-mediated polyubiquitination. PD-L1 N-terminal domains Ig-V and Ig-C but not the PD-L1 C-terminal tail co-IP’d with Chk2 and restored Chk1 inhibitor (Chk1i) treatment resistance. Tumor PD-L1 expression correlated with Chk1i sensitivity in 44 primary human small cell lung cancer cell lines, implicating tumor-intrinsic PD-L1 as a DDRi response biomarker. In WT mice, genetic PD-L1 depletion but not surface PD-L1 blockade with αPD-L1, sensitized immunotherapy-resistant, BRCA1-WT 4T1 tumors to PARP inhibitor (PARPi). PARPi effects were reduced on PD-L1 KO tumors in RAG2KO mice indicating immune-dependent DDRi efficacy. Tumor PD-L1 depletion, likely due to impaired DDR, enhanced PARPi induced tumor-intrinsic STING activation (e.g., p-TBK1, CCL5) suggesting potential to augment immunotherapies.ConclusionsWe challenge the prevailing surface PD-L1 paradigm and establish a novel mechanism for cell-intrinsic PD-L1 control of the DDR and gene product expression. We identify therapeutic vulnerabilities from tumor PD-L1 depletion utilizing small molecule DDRi currently being tested in clinical trials. Data could explain αPD-L1/DDRi treatment resistance. Intracellular PD-L1 could be a pharmacologically targetable treatment target and/or response biomarker for selective DDRi alone plus other immunotherapies.ReferencesTopalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16:275–287, doi:10.1038/nrc.2016.36 (2016).Clark CA, et al. Tumor-intrinsic PD-L1 signals regulate cell growth, pathogenesis and autophagy in ovarian cancer and melanoma. Canres 0258.2016 (2016).Gupta HB et al. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. 1, 16030 (2016).Zhu H, et al. BET bromodomain inhibition promotes anti-tumor immunity by suppressing PD-L1 expression. Cell Rep 16:2829–2837, doi:10.1016/j.celrep.2016.08.032 (2016)Wu B, et al. Adipose PD-L1 modulates PD-1/PD-L1 checkpoint blockade immunotherapy efficacy in breast cancer. Oncoimmunology 7:e1500107, doi:10.1080/2162402X.2018.1500107 (2018)Liang J, et al. Verteporfin inhibits PD-L1 through autophagy and the STAT1-IRF1-TRIM28 signaling axis, exerting antitumor efficacy. Cancer Immunol Res 8:952–965, doi:10.1158/2326-6066.CIR-19-0159 (2020)

scholarly journals miR-211 facilitates platinum chemosensitivity by blocking the DNA damage response (DDR) in ovarian cancer

2019 ◽  
Vol 10 (7) ◽  
Author(s):  
Tianzhen Wang ◽  
Dapeng Hao ◽  
Shucai Yang ◽  
Jianhui Ma ◽  
Weiwei Yang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Damage Response

Abstract 3641: The predictive and prognostic roles of DNA damage response genes in epithelial ovarian cancer

2012 ◽  
Author(s):  
Nicolette G. Alkema ◽  
Marieke Everts ◽  
Ate G.J. van der Zee ◽  
Klaske A. ten Hoor ◽  
Harry Hollema ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Epithelial Ovarian Cancer ◽  
Dna Damage Response ◽  
Damage Response

scholarly journals Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity

2018 ◽  
Vol 315 (3) ◽  
pp. F469-F478 ◽  
Author(s):  
Liping Sun ◽  
Jing Liu ◽  
Yanggang Yuan ◽  
Xinzhou Zhang ◽  
Zheng Dong
Keyword(s):  
Dna Damage ◽  
Histone Acetylation ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
The Body ◽  
Heme Oxygenase 1 ◽  
Antioxidant Genes ◽  
Cisplatin Nephrotoxicity ◽  
Damage Response ◽  
Induced Apoptosis

As a potent chemotherapy drug, cisplatin is also notorious for its side-effects including nephrotoxicity in kidneys, presenting a pressing need to identify renoprotective agents. Cisplatin nephrotoxicity involves epigenetic regulations, including changes in histone acetylation. Bromodomain and extraterminal (BET) proteins are “readers” of the epigenetic code of histone acetylation. Here, we investigated the potential renoprotective effects of JQ1, a small molecule inhibitor of BET proteins. We show that JQ1 significantly ameliorated cisplatin-induced nephrotoxicity in mice as indicated by the measurements of kidney function, histopathology, and renal tubular apoptosis. JQ1 also partially prevented the body weight loss during cisplatin treatment in mice. Consistently, JQ1 inhibited cisplatin-induced apoptosis in renal proximal tubular cells. Mechanistically, JQ1 suppressed cisplatin-induced phosphorylation or activation of p53 and Chk2, key events in DNA damage response. JQ1 also attenuated cisplatin-induced MAP kinase (p38, ERK1/2, and JNK) activation. In addition, JQ1 enhanced the expression of antioxidant genes including nuclear factor erythroid 2-related factor 2 and heme oxygenase-1, while diminishing the expression of the nitrosative protein inducible nitric oxide synthase. JQ1 did not suppress cisplatin-induced apoptosis in A549 nonsmall cell lung cancer cells and AGS gastric cancer cells. These results suggest that JQ1 may protect against cisplatin nephrotoxicity by suppressing DNA damage response, p53, MAP kinases, and oxidative/nitrosative stress pathways.

scholarly journals Tribbles 2 mediates cisplatin sensitivity and DNA damage response in epithelial ovarian cancer

2017 ◽  
Vol 141 (8) ◽  
pp. 1600-1614 ◽  
Author(s):  
Daniel Kritsch ◽  
Franziska Hoffmann ◽  
Daniel Steinbach ◽  
Lars Jansen ◽  
Stella Mary Photini ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Epithelial Ovarian Cancer ◽  
Dna Damage Response ◽  
Damage Response ◽  
Cisplatin Sensitivity
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