HPV-type-specific response of cervical cancer cells to cisplatin after silencing replication licensing factor MCM4
- 245 Downloads
Minichoromosome maintenance (MCM) proteins play key role in cell cycle progression by licensing DNA replication only once per cell cycle. These proteins are found to be overexpressed in cervical cancer cells. In this study, we depleted MCM4, one of the MCM 2–7 complex components by RNA interference (RNAi) in four cervical cancer cell lines. The four cell lines were selected on the basis of their human papillomavirus (HPV) infection: HPV16-positive SiHa, HPV18-positive ME-180, HPV16- and HPV18-positive CaSki, and HPV-negative C-33A. The MCM4-deficient cells irrespective of their HPV status grow for several generations and maintain regular cell cycle. We did not find any evidence of augmented response to a short-term (48 h) cisplatin treatment in these MCM4-deficient cells. However, MCM4−/HPV16+ SiHa cells cannot withstand a prolonged treatment (up to 5 days) of even a sublethal dosage of cisplatin. They show increased chromosomal instability compared to their control counterparts. On the other hand, MCM4-deficient CaSki cells (both HPV16+ and 18+) remain resistant to a prolonged exposure to cisplatin. Our study indicates that cervical cancer cells may be using excess MCMs as a backup for replicative stress; however, its regulatory mechanism is dependent on the HPV status of the cells.
KeywordsCervical cancer HPV status MCM4 RNA interference Cisplatin Chromosomal instability
The authors thankfully acknowledge the financial support from the Department of Biotechnology, Government of India (vide project no. BT/PR9246/Med/30/17/2007), to GN, SS, and SP; Banaras Hindu University (XIth Plan) to SS; Council of Scientific and Industrial Research, Government of India, for research fellowship to MD; and Interdisciplinary School of Life Sciences, Faculty of Science, Banaras Hindu University for equipment facilities.
Conflicts of interest
- 4.Das M, Singh S, Pradhan S, Narayan G. MCM Paradox: abundance of eukaryotic replicative helicases and genomic integrity. Mol Biol International. 2014:574850.Google Scholar
- 16.Shukla S, Bharti AC, Mahata S, Hussain S, Hedau S, Sharma R, et al. Application of a multiplex PCR to cervical cells collected by a paper smear for the simultaneous detection of all mucosal human papillomaviruses (HPVs) and typing of high-risk HPV types 16 and 18. J Med Microbiol. 2010;59:1303–10.CrossRefPubMedGoogle Scholar
- 24.Nicholas S E, Schwacha A. The Mcm2-7 replicative helicase: a promising chemotherapeutic target. BioMed Res International. 2014:549719.Google Scholar