HIF-1α inhibition sensitizes pituitary adenoma cells to temozolomide by regulating MGMT expression

Abstract

Suppression of hypoxia-inducible factor 1α (HIF-1α) has been shown to sensitize glioblastoma cells to temozolomide (TMZ) treatment via down-modulation of O6-methylguanine-DNA methyltransferase (MGMT) expression. To date, whether the efficacy of TMZ therapy is correlated with MGMT expression and whether HIF-1α suppression exerts similar effects in human pituitary adenoma cells have not been defined. In the present study, using an HIF-1α knockdown strategy and the HIF-1α inhibitor 2-methoxyestradiol (2ME), we demonstrated for the first time that HIF-1α suppression increases the efficacy of TMZ in human pituitary adenoma cells in vitro and in vivo. Our mechanistic study showed that HIF-1α suppression resulted in down-modulation of MGMT expression and decreased DNA damage repair ability as demonstrated by decreased RAD51 protein expression. These results suggest an HIF-1α-dependent regulation of MGMT expression in human pituitary adenoma cells, and HIF-1α knockdown or the HIF-1α inhibitor 2ME can confer TMZ sensitization in human pituitary adenomas. The clinical application of 2ME as an adjuvant therapy may be a potential approach to improve the efficacy of TMZ therapy for pituitary adenomas.