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 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.
Highlights
Metabolic reprogramming is a hallmark of cancer and apart from the well-known Warburg effect of aerobic glycolysis, several other metabolic adaptations have been described [1, 2]
Treatment with VEGFR2ki produced a slight increase in the levels of mitochondria-derived reactive oxygen species (ROS) (MitoSOX staining; Fig. 3H) and 8-hydroxyguanosine (8oxoG), an oxidized derivative of guanosine that is commonly used as a biomarker of oxidative stress (Fig. 3I) only in untreatedAML; whereas treatment with the less potent VEGFR2 inhibitor SU5614 was more effective in increasing mitochondrial-derived ROS (Supplementary Fig. S3O) and oxidative stress markers (Supplementary Fig. S3P). These results suggest that blocking VEGFR2 signaling increases mitochondrial biogenesis, function, and, to some extent, mitochondrial-derived ROS formation and oxidative stress in acute myeloid leukemia (AML), providing a rationale for the increased sensitivity to chemotherapy mediated by VEGFR2 inhibition in AML cells
Database platform, which revealed that patients with relatively low expression of proliferator–activated receptor gamma coactivator 1a (PGC-1a) had significantly worse overall survival than patients whose tumors expressed relatively high levels of PGC-1a (Supplementary Fig. S5), indicating that low expression of PGC-1a is an adverse clinical risk factor in AML. These results suggest that VEGFR2 signaling decreases the response of AML cells to chemotherapy by repressing proliferator–activated receptor gamma coactivator 1-alpha (PGC1a)–mediated mitochondrial biogenesis, revealing a new metabolic vulnerability that potentially can be exploited to overcome treatment resistance in AML
Summary
Metabolic reprogramming is a hallmark of cancer and apart from the well-known Warburg effect of aerobic glycolysis, several other metabolic adaptations have been described [1, 2]. The use of alternative carbon sources and the establishment of metabolic interactions within the tumor microenvironment are examples of adaptation to secondary microenvironments and pharmacologic treatments [1,2,3]. There is compelling evidence across several tumor types that quiescent "cancer stem cells" rely more exclusively on mitochondrial respiration and oxidative phosphorylation (OXPHOS) for energy production and display impaired glycolytic capacity [5,6,7,8]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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