Findings reveal a mitochondrial metabolic vulnerability that might be exploited to kill chemotherapy-resistant acute myeloid leukemia cells

Authors and Affiliations:

Sandrina Nóbrega-Pereira1, Francisco Caiado1, Tânia Carvalho1, Inês Matias1, Gonçalo Graça2, Luís Gafeira Gonçalves2, Bruno Silva-Santos1, Haakan Norell1 and Sérgio Dias1

Abstract:

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 PPARG coactivator 1α (PGC-1α), and fewer mitochondria than controls from untreated AML animals. These changes were linked to increased vascular endothelial growth factor receptor 2 (VEGFR-2) signaling that counteracted chemotherapy-driven cell death; blocking of VEGFR-2 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 VEGFR-2 inhibition. Collectively, this reveals a mitochondrial metabolic vulnerability with potential therapeutic applications against chemotherapy-resistant AML.

Journal: Cancer Research

Link: http://cancerres.aacrjournals.org/content/early/2017/12/09/0008-5472.CAN-17-1166.long