title: 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.
authors: Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China.
authors: Wenna
authors: W
authors: Chen
authors: Zheng
authors: Z
authors: Xiao
authors: Yachao
authors: Y
authors: Zhao
authors: Lina
authors: L
authors: Huang
authors: Ganqin
authors: G
authors: Du
mesh_terms: D000077584:2-Methoxyestradiol; D000328:Adult; D000818:Animals; D018906:Antineoplastic Agents, Alkylating; D002470:Cell Survival / Q000187:drug effects; D015254:DNA Modification Methylases / Q000096:biosynthesis* / Q000235:genetics; D045643:DNA Repair Enzymes / Q000096:biosynthesis* / Q000235:genetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics*; D008297:Male; D051379:Mice; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018906:Antineoplastic Agents, Alkylating; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D025521:Tumor Suppressor Proteins; D004958:Estradiol; D000077584:2-Methoxyestradiol; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide