Abstract 772: High MDC1 expression in cervical cancer cells can affect the chemo- and radiotherapeutic response as its depletion leads to increased cell death

Abstract

Abstract Cervical cancer is the third most frequent cancer and common cause of death in women worldwide. The work presented identifies mediator of DNA damage checkpoint 1 (MDC1) as an important molecular target to increase sensitivity of cervical cancer cells to chemo or radiotherapy. MDC1 functions as an adaptor protein for recruitment and retention of many other DNA damage repair proteins in ataxia telangiectasia mutated (ATM) pathway for double-stranded DNA damage repair. It is reported to be highly expressed in cervical cancer cells. Also, its expression tends to increase with increase in malignancy. We have studied in detail MDC1 mRNA expression in three cervical cancer cell lines, HeLa, SiHa and CasKi, in response to various genotoxic stresses including some known inhibitors, UV exposure or gamma irradiation through quantitative PCR. The cellular response to the DNA damage resulted in increase in MDC1 expression, which declined with increase in treatment time period. Protein expression and activation by Western blotting with anti-MDC1 and anti-phosphoMDC1 antibody indicated a higher level of phosphorylated as compared to unphosphorylated MDC1. The significance of this increase in MDC1 expression was studied by generating stable cell lines knocked down for MDC1 expression. The modified cell lines were assessed for apoptosis through various assays, including flow cytometry, and showed greater cell death in response to DNA damage. In summary, high MDC1 expression can significantly affect chemo or radiotherapeutic response and its inhibition can improve sensitivity to these treatments. Citation Format: Neeru Singh, Rashmi Bhakuni, Sivapriya Kirubakaran. High MDC1 expression in cervical cancer cells can affect the chemo- and radiotherapeutic response as its depletion leads to increased cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 772.