CACNA1C as a Prognostic Biomarker and Therapeutic Target in High-Grade Serous Ovari-an Cancer: Clinical Validation and Molecular Dynamics of Nifedipine Blockade

High-Grade Serous Ovarian Cancer (HGSOC) is the most lethal gynecological malignancy due to aggressive growth, widespread metastases, and high intra-tumoral heterogeneity. Poor prognosis is largely due to late diagnosis, hence there is an urgent need to identify novel biomarkers for screening, diagnosis, and monitoring. Here, we propose the voltage-dependent calcium channel hCaV1.2 encoded by CACNA1C as a potential biomarker and therapeutic target in HGSOC. Using IHC analysis for ten ovarian cancer patients, cytotoxicity assay, TCGA gene expression and survival analyses, homology modeling, molecular docking, Calcium channel membrane assembly and molecular dynamics simulations, we tested CACNA1C’s role in HGSOC progression and the effect of blocking on cancer cell survival.

We show that nifedipine (NIFE), a calcium channel blocker (CCB), had a tumor suppressive effect based on binding models predicted by three-dimensional computer assisted molecular modeling and in vitro validation using human HGSOC cell line. Using The Cancer Genome Atlas ovarian public cohort, we found CACNA1C mRNA expression strongly correlated with poor patient survival for late-stage and metastasis than primary. We also show strong correlation of CACNA1C protein expression using immunohistochemistry correlating with COH ovarian carcinomas patients’ disease progression. This research demonstrates that targeting HGSOC via CCBs may be therapeutically beneficial. By establishing further in vitro, in vivo, and clinical trials using FDA approved NIFE may be repurposed to target CACNA1C for HGSOC.