Τετάρτη 31 Ιανουαρίου 2018

VEGFR2-Mediated Reprogramming of Mitochondrial Metabolism Regulates the Sensitivity of Acute Myeloid Leukemia to Chemotherapy

Metabolic reprogramming is central to tumorigenesis, but whether chemotherapy induces metabolic features promoting recurrence remains unknown. We established a mouse xenograft model of human acute myeloid leukemia (AML) that enabled chemotherapy-induced regressions of established disease followed by lethal regrowth of more aggressive tumor cells. Human AML cells from terminally ill mice treated with chemotherapy (chemoAML) had higher lipid content, increased lactate production and ATP levels, reduced expression of peroxisome proliferator–activated receptor gamma coactivator 1α (PGC-1α), and fewer mitochondria than controls from untreated AML animals. These changes were linked to increased VEGFR2 signaling that counteracted chemotherapy-driven cell death; blocking of VEGFR2 sensitized chemoAML to chemotherapy (re-)treatment and induced a mitochondrial biogenesis program with increased mitochondrial mass and oxidative stress. Accordingly, depletion of PGC-1α in chemoAML cells abolished such induction of mitochondrial metabolism and chemosensitization in response to VEGFR2 inhibition. Collectively, this reveals a mitochondrial metabolic vulnerability with potential therapeutic applications against chemotherapy-resistant AML.Significance: These findings reveal a mitochondrial metabolic vulnerability that might be exploited to kill chemotherapy-resistant acute myeloid leukemia cells. Cancer Res; 78(3); 731–41. ©2017 AACR.

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