Abstract:
Cervical cancer is a major cause of death in women despite the advancement of current
treatment modalities. The conventional therapeutic agent, cisplatin (CCDP), is the standard treatment for CC; however, resistance often develops due to the cancer’s heterogeneity. Therefore, a
detailed elucidation of the specific molecular mechanisms driving CC is crucial for the development of targeted therapeutic strategies. Retinoblastoma binding protein 6 (RBBP6) is a potential
biomarker associated with cell proliferation and is upregulated in cervical cancer sites, exhibiting
apoptosis and dysregulated p53 expression. Furthermore, RBBP6 has been demonstrated to sensitize
cancer cells to radiation and certain chemotherapeutic agents by regulating the Bcl-2 gene, thus
suggesting a crosstalk among RBBP6/p53/BCL-2 oncogenic signatures. The present study, therefore,
investigated the relationship between cisplatin and RBBP6 expression in CC cells. Herein, we first
explored bioinformatics simulations and identified that the RBBP6/p53/BCL-2 signaling pathway
is overexpressed and correlated with CC. For further analysis, we explored the Genomics of Drug
Sensitivity in Cancer (GDSC) and found that most of the CC cell lines are sensitive to CCDP. To
validate these findings, RBBP6 was silenced in HeLa and Vero cells using RNAi technology, followed
by measurement of wild-type p53 and Bcl-2 at the mRNA level using qPCR. Cells co-treated with
cisplatin and siRBBP6 were subsequently analyzed for apoptosis induction and real-time growth
monitoring using flow cytometry and the xCELLigence system, respectively. Cancer cells in the cotreatment group showed a reduction in apoptosis compared to the cisplatin-treated group. Moreover,
the real-time growth monitoring revealed a reduced growth rate in RBBP6 knockdown cells treated
with cisplatin. Although wild-type p53 remained unchanged in the co-treatment group of cancer cells,
Bcl-2 was completely repressed, suggesting that RBBP6 is necessary for sensitizing cervical cancer
cells to cisplatin treatment by downregulating Bcl-2. The Vero cell population, which served as a
non-cancerous control cell line in this study, remained viable following treatment with both siRBBP6
and cisplatin. Findings from this study suggest that RBBP6 expression promotes cisplatin sensitivity
in HeLa cells through Bcl-2 downregulation. Knockdown of RBBP6 limits apoptosis induction and
delays cell growth inhibition in response to cisplatin. The knowledge obtained here has the potential
to help improve cisplatin efficacy through personalized administration based on the expression
profile of RBBP6 among individual patients.
