Suppression of cytochrome P450 4B1: An early event in adrenocortical tumorigenesis.

Abstract

Adrenocortical carcinoma is a rare neoplasm with a poor prognosis. Conversely, adrenocortical adenomas are common and benign. Despite their shared histologic origin, little evidence exists to suggest that adrenocortical adenoma arises from adrenocortical carcinoma. Recent genetic analyses of adrenocortical carcinoma have shown recurrent gene copy deletion of CYP4B1, a cytochrome P450 isozyme. This study investigates a potential role for CYP4B1 in modulating adrenocortical tumorigenesis and/or conferring chemoresistance to adrenocortical carcinomas. Using TaqMan, real-time quantitative polymerase chain reaction techniques, we investigated CYP4B1 expression in normal adrenal cortex (n = 10), histologically confirmed adrenocortical adenomas (n = 10), and adrenocortical carcinomas (n = 10). Adrenocortical carcinoma cell lines were enforced to express CYP4B1, and effects on cell death and enhanced mitotane and cisplatin sensitivity were tested. Gene expression analyses demonstrated suppression of CYP4B1 in 100% of both the adrenocortical adenomas (10/10) and adrenocortical carcinomas (10/10) tested. Average relative expression of CYP4B1 was decreased at 0.19 (0.01-0.50; P < .01) in adrenocortical adenomas and nearly absent in adrenocortical carcinomas (0.01; 0.00-0.05; P < .01). Protein expression correlated with mRNA expression. Ectopic expression of CYP4B1 promoted cytotoxicity and increased chemosensitivity in adrenocortical carcinoma cell lines. CYP4B1 is silenced in both benign and malignant adrenocortical tumors and may contribute to tumorigenesis and chemoresistance. Sensitization of adrenocortical carcinoma cells engineered to overexpress CYP4B1 further supports this notion.