Overexpression of CYP11A1 recover cell cycle distribution in kidney cancer cells

Abstract

Clear cell renal carcinoma is commonly known for its metastasis propensity to outspread to other organs and there are no symptoms in the early stage. Recent studies have shown that deficiencies of CYP11A1 expression can lead to fatal adrenal failure if not treated and are associated with downstream regulation in various cancer types. However, the molecular mechanisms between CYP11A1 and kidney cancer proliferation remained unclear. In this context, normal and renal carcinoma cell lines (Hek293 and Caki-1) were transfected with CYP11A1 to stimulate overexpression. Cell cycle distribution was investigated by flow cytometry. Western blot analyses were performed to search for the related signaling pathways. We observed that CYP11A1 suppressed the expression of cyclin B1 and phosphorylation of Cdc2 but the cyclin-dependent kinases (Cdk2 and Cdk4) were not altered. Cancer cell migration and invasion were suppressed along with epithelial-intermediate metastatic markers snail and vimentin. In addition, CYP11A1 overexpression may play a role in promoting the activation of ATM while phosphorylation of upstream signals related to G2/M blocking (e.g., phosphorylation of Cdc25C tyrosine phosphatase at Ser216) may be activated by ATM checkpoint kinase. We first identified that the ERK1/2-ATM/ATR-Cdc25C pathway is an important mechanism for G2/M arrest in CYP11A1 overexpressed cell-based models. This finding might suggest that a promising new therapeutic target to suppress kidney cancer proliferation but has little effect on normal cells; thus, to improve the survival rate of cancer patients.