MDC1 depletion promotes Cisplatin induced cell death in Cervical cancer cells

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.

Recent advances and future directions in anti‐tumor activity of cryptotanshinone: A mechanistic review

“…The sophoridine is a plant derived‐natural compound that enhances sensitivity of lung cancer cells into cisplatin via induction of p53 and Hippo signaling pathways (Zhu et al, 2020). The mediator of DNA damage checkpoint 1 (MDC1) is a genetic factor that its down‐regulation induces apoptosis in cervical cancer cells (Singh, Bhakuni, Chhabria, & Kirubakaran, 2020). It is worth mentioning that CT can target molecular pathways to increase cisplatin sensitivity.…”

FD-895 and Pladienolide B Modulate RNA Splicing Associated With Wnt Signaling Pathway

“…Next, we turned our attention to explore the activity of splice modulation on cell lines displaying sensitivity or resistance to cisplatin, as the latter is an issue in the treatment of solid tumors including ovarian [34], cervical cancer [35], gastric adenocarcinoma[36], prostate cancer [37], colorectal [38], and head and neck squamous cell carcinoma [39]. Here, we used two human ovarian cancer cell lines, one consisting of a cisplatin-sensitive parental line, OV2008 and the other stably cisplatin-resistant subline, OV2008/C13 derived by in vitro selection with cisplatin.…”