Inhibition of EGFR nuclear translocation attenuate radioresistance through decreased p-DNA-PK expression in cervical cancer cells.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17011-e17011
Author(s):  
Yunxiang Qi ◽  
Jinyi Lang ◽  
Lu Li ◽  
Mei Feng ◽  
Yecai Huang
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Dna Damage Repair ◽  
Cervical Cancer Cell Line ◽  
Phosphorylation Level ◽  
Damage Repair ◽  
Cervical Cancer Cells

e17011 Background: The commonly used treatment for cervical cancer is radiotherapy. However, the resistance to irradiation and metastasis at the advanced stage is a common reason for the poor prognosis and high mortality. This study was designed to elucidate the role of epidermal growth factor receptor (EGFR) nuclear translocation in radioresistance, and its correlation with DNA damage repair pathway in the cervical cancer cells. Methods: The dynamic expression of EGFR, DNA-dependent protein kinase (DNA-PK), PDK-1, PKN1 and their phosphorylation level in irradiated cervical cancer cell line CaSki at 0 10 20 40 minutes was determined by western blotting. Besides, nuclear localization signal (NLS) peptide inhibitor and control peptides was synthesized and treated cells before irradiation to elucidate the correlation between EGFR nuclear translocation and DNA damage repair after irradiation. Results: Expression of EGFR, protein kinase N1 (PKN1), and DNA-PK in nucleus was increased after irradiation in CaSki cells. Irradiation also enhanced the phosphorylation level of EGFR at Thr654, PKN1 at T774 and DNA-PK at T2609. Inhibition of EGFR nuclear translocation by NLS peptide decreased the expression level of EGFR and DNA-PK in the nucleus, and attenuated their phosphorylation process. Conclusions: EGFR nuclear translocation riggered by irradiation promoted DNA damage repair in irradiated cervical cancer cells. This work facilitated us to understand the possible molecular mechanism of the resistance to irradiation in the treatment of cervical cancer, providing a potentially potent clinical method to cancer therapy.

scholarly journals MDC1 depletion promotes Cisplatin induced cell death in Cervical cancer cells

2020 ◽  
Author(s):  
Neeru Singh ◽  
Rashmi Bhakuni ◽  
Dimple Chhabria ◽  
sivapriya kirubakaran
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Prognosis ◽  
Double Stranded Dna ◽  
Damage Repair ◽  
Cervical Cancer Cells ◽  
Cisplatin Sensitivity ◽  
Functional Dna

Abstract Objective: Cisplatin, the most common chemotherapeutic drug for the treatment of advanced stage cervical cancers has limitations in terms of drugs resistance observed in patients partly due to functional DNA damage repair (DDR) processes in the cell. Mediator of DNA damage checkpoint1 (MDC1) is an important protein in the Ataxia telangiectasia mutated (ATM) mediated double stranded DNA break (DSB) repair pathway. In this regard, we investigated the effect of MDC1change in expression on the cisplatin sensitivity in cervical cancer cells. Results: Through modulation of MDC1 expression in the cervical cancer cell lines; Hela, SiHa and Caski, we found that all the three cell lines silenced for MDC1 exhibited higher sensitivity to cisplatin treatment with inefficiency in accumulation of p γH2AX, Ser 139 foci and increased accumulation of pChk2 Thr 68 at the damaged chromatin followed by enhanced apoptosis. Further, we observed the increased p53 Ser 15 phosphorylation in the MDC1 depleted cells. Our studies suggest that MDC1 expression could be a key determinant in cervical cancer prognosis and treatment and its depletion in combination with cisplatin has the potential to be explored for the sensitisation of chemo-resistant cervical cancer cells.

scholarly journals MDC1 depletion promotes Cisplatin induced cell death in Cervical cancer cells

2020 ◽  
Author(s):  
Neeru Singh ◽  
Rashmi Bhakuni ◽  
Dimple Chhabria ◽  
Sivapriya Kirubakaran
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Prognosis ◽  
Double Stranded Dna ◽  
Damage Repair ◽  
Cervical Cancer Cells ◽  
Cisplatin Sensitivity ◽  
Functional Dna

Abstract Objective: Cisplatin, the most common chemotherapeutic drug for the treatment of advanced stage cervical cancers has limitations in terms of drugs resistance observed in patients partly due to functional DNA damage repair (DDR) processes in the cell. Mediator of DNA damage checkpoint1 (MDC1) is an important protein in the Ataxia telangiectasia mutated (ATM) mediated double stranded DNA break (DSB) repair pathway. In this regard, we investigated the effect of MDC1change in expression on the cisplatin sensitivity in cervical cancer cells.Results: Through modulation of MDC1 expression in the cervical cancer cell lines; Hela, SiHa and Caski, we found that all the three cell lines silenced for MDC1 exhibited higher sensitivity to cisplatin treatment with inefficiency in accumulation of p γH2AX, Ser 139 foci and increased accumulation of pChk2 Thr 68 at the damaged chromatin followed by enhanced apoptosis. Further, we observed the increased p53 Ser 15 phosphorylation in the MDC1 depleted cells. Our studies suggest that MDC1 expression could be a key determinant in cervical cancer prognosis and treatment and its depletion in combination with cisplatin has the potential to be explored for the sensitisation of chemo-resistant cervical cancer cells.

scholarly journals Insights of Cisplatin Resistance in Cervical Cancer: A Decision Making for Cellular Survival

2021 ◽  
Author(s):  
Elizabeth Mahapatra ◽  
Salini Das ◽  
Souvick Biswas ◽  
Archismaan Ghosh ◽  
Debomita Sengupta ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Platinum Resistance ◽  
Cellular Survival ◽  
Repair Enzymes ◽  
Damage Repair ◽  
Cervical Cancer Cells ◽  
The Impact

The clinical scenario of acquired cisplatin resistance is considered as a major impediment in cervical cancer treatment. Bulky drug-DNA adducts formed by cisplatin elicits DNA damage response (DDR) which either subsequently induces apoptosis in the cervical cancer cells or enables them to adapt with drug assault by invigorating pro-survival molecular cascades. When HPV infected cervical cancer cells encounter cisplatin, a complex molecular interaction between deregulated tumor suppressors, DNA damage-repair enzymes, and prosurvival molecules get initiated. Ambiguous molecular triggers allow cancer cells to cull apoptosis by opting for a survival fate. Overriding of the apoptotic cues by the pro-survival cues renders a cisplatin resistant phenotype in the tumor microenvironment. The present review undrapes the impact of deregulated signaling nexus formed due to crosstalk of the key molecules related to cell survival and apoptosis in orchestrating platinum resistance in cervical cancer.

CYT-Rx20 Inhibits Cervical Cancer Cell Growth and Migration Through Oxidative Stress-Induced DNA Damage, Cell Apoptosis, and Epithelial-to-Mesenchymal Transition Inhibition

2017 ◽  
Vol 27 (7) ◽  
pp. 1306-1317
Author(s):  
Yen-Yun Wang ◽  
Pei-Wen Hsieh ◽  
Yuk-Kwan Chen ◽  
Stephen Chu-Sung Hu ◽  
Ya-Ling Hsu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Apoptosis ◽  
Cervical Cancer Cell ◽  
Ros Generation ◽  
Mesenchymal Transition ◽  
Cervical Cancer Cells

ObjectiveThe β-nitrostyrene family has been reported to possess anticancer properties. However, the anticancer activity of β-nitrostyrenes on cervical cancer cells and the underlying mechanisms involved remain unexplored. In this study, a β-nitrostyrene derivative CYT-Rx20 (3′-hydroxy-4′-methoxy-β-methyl-β-nitrostyrene) was synthesized, and its anticancer activity on cervical cancer cells and the mechanisms involved were investigated.MethodsThe effect of CYT-Rx20 on human cervical cancer cell growth was evaluated using cell viability assay. Reactive oxygen species (ROS) generation and annexin V staining were detected by flow cytometry. The protein expression levels of cleaved caspase-3, cleaved caspase-9, cleaved poly (ADPribose) polymerase, γH2AX, β-catenin, Vimentin, and Twist were measured by Western blotting. DNA double-strand breaks were determined by γ-H2AX foci formation and neutral comet assay. Migration assay was used to determine cancer cell migration. Nude mice xenograft was used to investigate the antitumor effects of CYT-Rx20 in vivo.ResultsCYT-Rx20 induced cytotoxicity in cervical cancer cells by promoting cell apoptosis via ROS generation and DNA damage. CYT-Rx20-induced cell apoptosis, ROS generation, and DNA damage were reversed by thiol antioxidants. In addition, CYT-Rx20 inhibited cervical cancer cell migration by regulating the expression of epithelial-to-mesenchymal transition markers. In nude mice, CYT-Rx20 inhibited cervical tumor growth accompanied by increased expression of DNA damage marker γH2AX and decreased expression of mesenchymal markers β-catenin and Twist.ConclusionsCYT-Rx20 inhibits cervical cancer cells in vitro and in vivo and has the potential to be further developed into an anti-cervical cancer drug clinically.

scholarly journals Xanthohumol Induces Growth Inhibition and Apoptosis in Ca Ski Human Cervical Cancer Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Wai Kuan Yong ◽  
Sri Nurestri Abd Malek
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Morphological Changes ◽  
S Phase ◽  
Phase Cell ◽  
Cervical Cancer Cell Line ◽  
Dependent Manner ◽  
Cervical Cancer Cells

We investigate induction of apoptosis by xanthohumol on Ca Ski cervical cancer cell line. Xanthohumol is a prenylated chalcone naturally found in hop plants, previously reported to be an effective anticancer agent in various cancer cell lines. The present study showed that xanthohumol was effective to inhibit proliferation of Ca Ski cells based on IC50values using sulforhodamine B (SRB) assay. Furthermore, cellular and nuclear morphological changes were observed in the cells using phase contrast microscopy and Hoechst/PI fluorescent staining. In addition, 48-hour long treatment with xanthohumol triggered externalization of phosphatidylserine, changes in mitochondrial membrane potential, and DNA fragmentation in the cells. Additionally, xanthohumol mediated S phase arrest in cell cycle analysis and increased activities of caspase-3, caspase-8, and caspase-9. On the other hand, Western blot analysis showed that the expression levels of cleaved PARP, p53, and AIF increased, while Bcl-2 and XIAP decreased in a dose-dependent manner. Taken together, these findings indicate that xanthohumol-induced cell death might involve intrinsic and extrinsic apoptotic pathways, as well as downregulation of XIAP, upregulation of p53 proteins, and S phase cell cycle arrest in Ca Ski cervical cancer cells. This work suggests that xanthohumol is a potent chemotherapeutic candidate for cervical cancer.

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