mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 1; pp. 409 - 414
• Main Authors: Weiler, Markus, Blaes, Jonas, Pusch, Stefan, Sahm, Felix, Czabanka, Marcus, Luger, Sebastian, Bunse, Lukas, Solecki, Gergely, Eichwald, Viktoria, Jugold, Manfred, Hodecker, Sibylle, Osswald, Matthias, Meisner, Christoph, Hielscher, Thomas, Rübmann, Petra, Pfenning, Philipp-Niklas, Ronellenfitsch, Michael, Kempf, Tore, Schnölzer, Martina, Abdollahi, Amir, Lang, Florian, Bendszus, Martin, von Deimling, Andreas, Winkler, Frank, Weller, Michael, Vajkoczy, Peter, Platten, Michael, Wick, Wolfgang
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.01.2014; National Acad Sciences
• Subjects: adrenal cortex hormones; Animals; Antineoplastic Agents, Alkylating - pharmacology; Biological Sciences; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Cell Cycle Proteins - metabolism; Cell lines; Chemotherapy; chronic exposure; Corticoids; DNA Repair; Drug resistance; Drug Resistance, Neoplasm; drug therapy; Enzymes; Gene expression; Gene Expression Regulation, Neoplastic; genes; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioma; Glioma - drug therapy; Glioma - metabolism; HEK293 cells; Humans; Hypoxia; Immunoblotting; Intracellular Signaling Peptides and Proteins - metabolism; Irradiation; Lentivirus - metabolism; mammals; methylation; methyltransferases; Mice; Mice, Nude; Neoplasm Transplantation; O-Methylguanine-DNA Methyltransferase - pharmacology; patients; Phosphorylation; Plasmids - metabolism; Radiotherapy; Steroids; Time Factors; TOR Serine-Threonine Kinases - metabolism; Tumors
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1314469111

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.