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Targeting tumor mitochondrial metabolism overcomes resistance to antiangiogenics

ABSTRACT: Epithelial malignancies are effectively treated by antiangiogenics; however, acquired resistance is a major problem in cancer therapeutics. Epithelial tumors commonly have mutations in the MAPK/Pi3K-AKT pathways, which leads to high-rate aerobic glycolysis. Here, we show how novel multikinase inhibitor antiangiogenics (TKIs) induce hypoxia correction in spontaneous breast and lung tumor models. When this happens, the tumors down-regulate glycolysis and switch to long-term reliance on mitochondrial respiration. A transcriptomic, metabolomic and phosphoproteomic study revealed that this metabolic switch is mediated by down-regulation of HIF1α and AKT and up-regulation of AMPK, allowing uptake and degradation of fatty acids and ketone bodies. The switch renders mitochondrial respiration necessary for tumor survival. Agents like phenformin or ME344 induce synergistic tumor control when combined with TKIs, especially in a sequential schedule, leading to metabolic synthetic lethality. Our study uncovers new mechanistic insights in the process of tumor resistance to TKIs, and may have clinical applicability.

ORGANISM(S): Mus musculus

PROVIDER: GSE80778 | GEO | 2019/04/26

REPOSITORIES: GEO

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Targeting tumor mitochondrial metabolism overcomes resistance to antiangiogenics

Project description:Epithelial malignancies are effectively treated by antiangiogenics; however, acquired resistance is a major problem in cancer therapeutics. Epithelial tumors commonly have mutations in the MAPK/Pi3K-AKT pathways, which leads to high-rate aerobic glycolysis. Here, we show how novel multikinase inhibitor antiangiogenics (TKIs) induce hypoxia correction in spontaneous breast and lung tumor models. When this happens, the tumors down-regulate glycolysis and switch to long-term reliance on mitochondrial respiration. A transcriptomic, metabolomic and phosphoproteomic study revealed that this metabolic switch is mediated by down-regulation of HIF1α and AKT and up-regulation of AMPK, allowing uptake and degradation of fatty acids and ketone bodies. The switch renders mitochondrial respiration necessary for tumor survival. Agents like phenformin or ME344 induce synergistic tumor control when combined with TKIs, especially in a sequential schedule, leading to metabolic synthetic lethality. Our study uncovers new mechanistic insights in the process of tumor resistance to TKIs, and may have clinical applicability

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MITOCHONDRIAL Akt REGULATION OF HYPOXIC METABOLIC REPROGRAMMING

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Project description:The Warburg effect, consisting of increased glucose uptake and glycolysis, provides metabolic energy as well as cellular building blocks for tumor growth. Inhibition of the Warburg effect with 2-deoxyglucose (2DG) has been explored in clinical trials with limited efficacy. Blockage of glycolysis can induce autopahgy resulting in alternative energy generation through oxidative phosphorylation providing a potential bypass of the effects of inhibition of glycolysis. Here in we demonstrate that activation of AMPK, as a consequence of energetic stress, induces mitochondrial energy production potentially bypassing the effects of glycolysis inhibition. We thus combined blockage of glycolysis by 2DG with inhibition of the electron transfer complex I (ETC1) in the mitochondria with the clinically applicable antidiabetic drug metformin. The combination resulted in activation of AMPK and autopahgy that however rendered eventual depletion of ATP and cell death. Furthermore, combined inhibition of glycolysis and mitochondrial respiration inhibited tumor growth and markedly decreased metastatic capacity in vivo. In order to understand the mechanism of these metabolic inhibitors, we performed whole genome transcriptional analysis. Human SK-4 esophageal cancer cell lines were treated with 5 different treatment groups [2 deoxy glucose (4mM), Metformin (5mM), AICAR (2mM), 2 deoxy glucose (4mM) plus Metformin (5mM) and 2 deoxy glucose (4mM) plus AICAR (2mM)] with non treated control groups for 12 hrs. Each groups was quadruplicated. Microarray experiments and data analysis were done at Dept. of Systems Biology, MDACC (Houston, USA)

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