German Cancer Consortium, Clinical Cooperation Units Neurooncology and Neuropathology, Helmholtz Group Experimental Neuroimmunology, Small Animal Imaging Facility, Biostatistics, and Functional Proteome Analysis, German Cancer Research Center, D-69120 Heidelberg, Germany.
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):409-14. doi: 10.1073/pnas.1314469111. Epub 2013 Dec 23.
A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O(6)-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids.
缺氧微环境通过激活哺乳动物雷帕霉素靶蛋白（mTOR）通路中的靶标诱导对烷化剂的耐药性。然而，这种 mTOR 介导的缺氧诱导的化疗耐药性的分子机制尚不清楚。在这里，我们确定 mTOR 靶标 N- myc 下游调节基因 1（NDRG1）是对烷化化疗耐药的关键决定因素，这种耐药性是由缺氧驱动的，但也由治疗措施驱动，如放疗、皮质类固醇和通过涉及缺氧诱导因子（HIF）-1α、p53 和 mTOR 复合物 2（mTORC2）/血清糖皮质激素诱导蛋白激酶 1（SGK1）通路的慢性暴露于烷化剂。对烷化化疗的耐药性而不是放疗依赖于 NDRG1 的表达和活性。在恶性神经胶质瘤患者的治疗后肿瘤组织中，NDRG1 被诱导，并且对烷化化疗的反应不良具有预测性。在分子水平上，NDRG1 结合并稳定了甲基转移酶，主要是 O（6）-甲基鸟嘌呤-DNA 甲基转移酶（MGMT），这是胶质母细胞瘤患者对烷化剂耐药的关键酶。在胶质母细胞瘤患者中，肿瘤组织中 MGMT 启动子的甲基化并不能更准确地预测接受皮质类固醇联合治疗的患者对烷化化疗的反应。
