Singh Neeru, Bhakuni Rashmi, Chhabria Dimple, Kirubakaran Sivapriya
Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat, 382355, India.
Indian Institute of Technology Gandhinagar, Palaj Campus, Gandhinagar, Gujarat, 382355, India.
BMC Res Notes. 2020 Mar 11;13(1):146. doi: 10.1186/s13104-020-04996-5.
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 checkpoint 1 (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 MDC1 change in expression on the cisplatin sensitivity in cervical cancer cells.
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 its depletion in combination with cisplatin has the potential to be explored for the sensitisation of chemo-resistant cervical cancer cells.
顺铂是治疗晚期宫颈癌最常用的化疗药物，但在患者中观察到耐药性方面存在局限性，部分原因是细胞中的功能性DNA损伤修复（DDR）过程。DNA损伤检查点1（MDC1）的介质是共济失调毛细血管扩张突变（ATM）介导的双链DNA断裂（DSB）修复途径中的一种重要蛋白质。在这方面，我们研究了MDC1表达变化对宫颈癌细胞顺铂敏感性的影响。
通过调节宫颈癌细胞系Hela、SiHa和Caski中MDC1的表达，我们发现所有三种MDC1沉默的细胞系对顺铂治疗表现出更高的敏感性，pγH2AX、Ser 139位点的积累效率低下，受损染色质上pChk2 Thr 68的积累增加，随后凋亡增强。此外，我们观察到MDC1缺失细胞中p53 Ser 15磷酸化增加。我们的研究表明，MDC1表达可能是宫颈癌预后的关键决定因素，其缺失与顺铂联合使用有可能用于探索化疗耐药宫颈癌细胞的致敏作用。
