mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy

摘要: A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify mTOR N-myc downstream regulated gene 1 (NDRG1) as a key determinant toward chemotherapy, driven hypoxia but also therapeutic measures such irradiation, corticosteroids, and chronic exposure via distinct routes involving hypoxia-inducible factor (HIF)-1alpha, p53, complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase (SGK1) Resistance chemotherapy not radiotherapy was dependent on NDRG1 expression activity. In posttreatment tumor tissue patients with malignant gliomas, induced predictive poor response chemotherapy. On level, bound stabilized methyltransferases, chiefly O6-methylguanine-DNA methyltransferase (MGMT), enzyme for glioblastoma patients. glioblastoma, MGMT promoter methylation more who received concomitant corticosteroids.