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HPV-type-specific response of cervical cancer cells to cisplatin after silencing replication licensing factor MCM4
Mitali Das1, Shyam Babu Prasad1,2, Suresh Singh Yadav1
1Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221 005, Uttar Pradesh, India.
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.
Insights
Minichoromosome maintenance (MCM) proteins are overexpressed in cervical cancer. Depleting MCM4 in cancer cells revealed that HPV status influences cisplatin resistance and chromosomal instability, suggesting MCMs act as a backup for replicative stress.
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Genetics
Background:
- Minichromosome maintenance (MCM) proteins are essential for DNA replication licensing.
- Overexpression of MCM proteins is observed in various cancers, including cervical cancer.
- The role of MCM proteins in cervical cancer progression and treatment response remains incompletely understood.
Purpose of the Study:
- To investigate the functional role of MCM4 depletion in cervical cancer cell lines with varying human papillomavirus (HPV) statuses.
- To determine the impact of MCM4 deficiency on cell cycle progression and response to cisplatin treatment.
- To elucidate the relationship between MCM4, HPV status, and replicative stress resilience in cervical cancer.
Main Methods:
- RNA interference (RNAi) was used to deplete MCM4 in four cervical cancer cell lines (SiHa, ME-180, CaSki, C-33A) with different HPV infections.
- Cell cycle progression was monitored in MCM4-deficient cells.
- Cisplatin treatment (short-term and prolonged) was administered to assess drug response and chromosomal instability.
Main Results:
- MCM4-deficient cells maintained normal cell cycle progression regardless of HPV status.
- Short-term cisplatin treatment did not show augmented sensitivity in MCM4-deficient cells.
- Prolonged cisplatin treatment induced chromosomal instability in MCM4-deficient HPV16-positive SiHa cells, while MCM4-deficient CaSki cells (HPV16+/18+) remained resistant.
Conclusions:
- Cervical cancer cells may utilize excess MCM proteins as a compensatory mechanism against replicative stress.
- The regulatory mechanism of MCMs in response to stress and chemotherapy is dependent on the HPV status of the cancer cells.
- Targeting MCM proteins could be a potential therapeutic strategy, but its efficacy may vary based on HPV infection.
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