Year: 2013
Type: article
Abstract: 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.
Authors: Markus Weiler, Jonas Blaes, Stefan Pusch, Felix Sahm, Marcus Czabanka, Sebastian Luger, Lukas Bunse, Gergely Solecki, Viktoria Eichwald, Manfred Jugold, Sibylle Hodecker, Matthias Osswald, Christoph Meisner, Thomas Hielscher, Petra Rübmann, Philipp-Niklas Pfenning, Michael Ronellenfitsch, Tore Kempf, Martina Schnölzer, Amir Abdollahi, Florian Lang, Martin Bendszus, Andreas von Deimling, Frank Winkler, Michael Weller, Peter Vajkoczy, Michael Platten, Wolfgang Wick
Institutions: Deutsches Konsortium für Translationale Krebsforschung, Charité - Universitätsmedizin Berlin, Goethe University Frankfurt, University Hospital Frankfurt, German Cancer Research Center, National Center for Tumor Diseases, University of Tübingen, University Hospital Heidelberg, University Hospital Zurich
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2024930656