Notch1 inhibition enhances DNA damage induced by cisplatin in cervical cancer

• Published in: Experimental cell research 2019-03, Vol.376 (1), p.27-38
• Main Authors: Li, ShiRong, Ren, Bo, Shi, Yue, Gao, Hang, Wang, JianWei, Xin, Ying, Huang, Bo, Liao, SuChan, Yang, YanPing, Xu, ZhiXiang, Li, Yulin, Zeng, Qinghua
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - drug effects; Ataxia Telangiectasia Mutated Proteins - genetics; ATM; Cell Proliferation - drug effects; Cervical cancer; Checkpoint Kinase 2 - genetics; Cisplatin; Cisplatin - adverse effects; Cisplatin - pharmacology; Diamines - pharmacology; DNA Damage - drug effects; DNA Damage - genetics; DNA damage response; Female; Gene Expression Regulation, Neoplastic - drug effects; HeLa Cells; Humans; Notch1; Receptor, Notch1 - antagonists & inhibitors; Receptor, Notch1 - genetics; Thiazoles - pharmacology; Tumor Suppressor Protein p53 - genetics; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - pathology
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2019.01.014

The expression of Notch1 plays an important role in the occurrence and development of various tumors. Previous studies have shown that Notch1 plays a negative regulatory role in response to radiation-induced DNA damage responses. It also has been reported that Notch1 was highly expressed in cervical cancer. It is well known that the first-line chemotherapy drug for treating cervical cancer, cisplatin, targets double-stranded DNA and induces apoptosis in the cells. However, the tolerability of cisplatin is an issue to overcome in the treatment of cervical cancer. Cisplatin has been reported to induce the up-regulation of Notch1 intracellular domain (NICD) through the γ-proteolytic enzyme complex, a complex that mediates Notch1 activation. Therefore, whether Notch1 is highly expressed in the cells or cisplatin induced high expression of NICD in cervical cancer has not been specifically discussed in these studies. More importantly, whether the inhibition of Notch1 activation would enhance DNA damage induced by cisplatin and/or cellular apoptosis mediated via ATM/CHK2/P53 pathway has not been reported in cervical cancer. In this study, we observed an enhanced DNA damage and cellular apoptosis via the ATM/CHK2/P53 pathway(s) in HeLa and SiHa cells treated with cisplatin combined with DAPT of Notch1 inhibitor. Our findings provide an alternative therapeutic strategy for the treatment of cervical cancer in the clinic. •Cisplatin induced DNA damage and apoptosis through ATM-CHK2 -P53 pathway in cervical cancer cells.•Notch1 is involved in DNA damage induced by cisplatin in cervical cancer cells.•Notch1 inhibition enhances cisplatin-induced DNA damage and apoptosis in cervical cancer cells via the ATM-CHK2-P53 pathway.