title: HPV-type-specific response of cervical cancer cells to cisplatin after silencing replication licensing factor MCM4.
abstract: 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.
authors.affiliation: Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221 005, Uttar Pradesh, India.
authors.forename: Mitali
authors.initials: M
authors.lastname: Das
authors.affiliation: Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221 005, Uttar Pradesh, India.|Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, I-7, Sector-39, Noida, 201 301, India.
authors.forename: Shyam Babu
authors.initials: SB
authors.lastname: Prasad
authors.affiliation: Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221 005, Uttar Pradesh, India.
authors.forename: Suresh Singh
authors.initials: SS
authors.lastname: Yadav
authors.affiliation: Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221 005, Uttar Pradesh, India.
authors.forename: Arusha
authors.initials: A
authors.lastname: Modi
authors.affiliation: Department of Zoology, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi, 221 005, Uttar Pradesh, India.
authors.forename: Sunita
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Radiotherapy and Radiation Medicine, Banaras Hindu University, Varanasi, 221 005, Uttar Pradesh, India.
authors.forename: Satyajit
authors.initials: S
authors.lastname: Pradhan
authors.affiliation: Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221 005, Uttar Pradesh, India. gnarayan@bhu.ac.in.
authors.forename: Gopeshwar
authors.initials: G
authors.lastname: Narayan
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D052162:Human papillomavirus 16 / Q000187:drug effects / Q000235:genetics; D052161:Human papillomavirus 18 / Q000187:drug effects / Q000472:pathogenicity; D006801:Humans; D064148:Minichromosome Maintenance Complex Component 4 / Q000037:antagonists & inhibitors / Q000235:genetics*; D034622:RNA Interference; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000821:virology
chemical_list: C099243:MCM4 protein, human; D064148:Minichromosome Maintenance Complex Component 4; D002945:Cisplatin
keywords: Cervical cancer; Chromosomal instability; Cisplatin; HPV status; MCM4; RNA interference