Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer

• Published in: Oncogene Vol. 32; no. 13; pp. 1638 - 1650
• Main Authors: Sutendra, G, Dromparis, P, Kinnaird, A, Stenson, T H, Haromy, A, Parker, J M R, McMurtry, M S, Michelakis, E D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28-03-2013; Nature Publishing Group
• Subjects: 631/67/1059; 631/67/2327; 631/67/2328; 631/80/86; Angiogenesis; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Animal models; Animals; Apoptosis; Breast cancer; Cancer; Cell Biology; Cell culture; Cell Line, Tumor; Dehydrogenases; Dichloroacetic acid; Down-Regulation - drug effects; Down-Regulation - genetics; Enzyme inhibitors; Female; Gene Expression Regulation, Neoplastic - drug effects; Glycolysis; Human Genetics; Humans; Hydrogen peroxide; Hydroxylase; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Hypoxia-inducible factors; Internal Medicine; Ketoglutaric acid; Kinases; Medicine; Medicine & Public Health; Metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Models, Biological; Neoplasms - blood supply; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neovascularization, Pathologic - prevention & control; Non-small cell lung carcinoma; Oncology; original-article; Oxidation; p53 Protein; Perfusion; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pyruvic acid; Rats; Rats, Nude; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Small cell lung carcinoma; Solid tumors; Tumors; Xenograft Model Antitumor Assays; Xenografts; hypoxia-inducible-factor; tumor perfusion; vascularity; stem cell; mitochondria; angiogenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.198

Most solid tumors are characterized by a metabolic shift from glucose oxidation to glycolysis, in part due to actively suppressed mitochondrial function, a state that favors resistance to apoptosis. Suppressed mitochondrial function may also contribute to the activation of hypoxia-inducible factor 1α (HIF1α) and angiogenesis. We have previously shown that the inhibitor of pyruvate dehydrogenase kinase (PDK) dichloroacetate (DCA) activates glucose oxidation and induces apoptosis in cancer cells
in vitro
and
in vivo
. We hypothesized that DCA will also reverse the ‘pseudohypoxic’ mitochondrial signals that lead to HIF1α activation in cancer, even in the absence of hypoxia and inhibit cancer angiogenesis. We show that inhibition of PDKII inhibits HIF1α in cancer cells using several techniques, including HIF1α luciferase reporter assays. Using pharmacologic and molecular approaches that suppress the prolyl-hydroxylase (PHD)-mediated inhibition of HIF1α, we show that DCA inhibits HIF1α by both a PHD-dependent mechanism (that involves a DCA-induced increase in the production of mitochondria-derived α-ketoglutarate) and a PHD-independent mechanism, involving activation of p53 via mitochondrial-derived H
2
O
2
, as well as activation of GSK3β. Effective inhibition of HIF1α is shown by a decrease in the expression of several HIF1α regulated gene products as well as inhibition of angiogenesis
in vitro
in matrigel assays. More importantly, in rat xenotransplant models of non-small cell lung cancer and breast cancer, we show effective inhibition of angiogenesis and tumor perfusion
in vivo
, assessed by contrast-enhanced ultrasonography, nuclear imaging techniques and histology. This work suggests that mitochondria-targeting metabolic modulators that increase pyruvate dehydrogenase activity, in addition to the recently described pro-apoptotic and anti-proliferative effects, suppress angiogenesis as well, normalizing the pseudo-hypoxic signals that lead to normoxic HIF1α activation in solid tumors.