Mitochondrial retrograde signaling mediated by UCP2 inhibits cancer cell proliferation and tumorigenesis.

Abstract

Cancer cells tilt their energy production away from oxidative phosphorylation (OXPHOS) toward glycolysis during malignant progression, even when aerobic metabolism is available. Reversing this phenomenon, known as the Warburg effect, may offer a generalized anticancer strategy. In this study, we show that overexpression of the mitochondrial membrane transport protein UCP2 in cancer cells is sufficient to restore a balance toward oxidative phosphorylation and to repress malignant phenotypes. Altered expression of glycolytic and oxidative enzymes mediated the effects of this metabolic shift. Notably, UCP2 overexpression increased signaling from the master energy-regulating kinase, adenosine monophosphate-activated protein kinase, while downregulating expression of hypoxia-induced factor. In support of recent new evidence about UCP2 function, we found that UCP2 did not function in this setting as a membrane potential uncoupling protein, but instead acted to control routing of mitochondria substrates. Taken together, our results define a strategy to reorient mitochondrial function in cancer cells toward OXPHOS that restricts their malignant phenotype.

• Authors: Pauline Esteves, Claire Pecqueur, Céline Ransy, Catherine Esnous, Véronique Lenoir, Frédéric Bouillaud, Anne-Laure Bulteau, Anne Lombès, Carina Prip-Buus, Daniel Ricquier, Marie-Clotilde Alves-Guerra
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 14 Pg. 3971-82 (Jul 15 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24853548 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Hypoxia-Inducible Factor 1
• Ion Channels
• Mitochondrial Proteins
• UCP2 protein, human
• Ucp2 protein, mouse
• Uncoupling Protein 2
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Apoptosis
• Cell Cycle
• Cell Line, Tumor
• Cell Proliferation
• Cell Transformation, Neoplastic (genetics, metabolism)
• Gene Expression
• Humans
• Hypoxia-Inducible Factor 1 (metabolism)
• Ion Channels (genetics, metabolism)
• Melanoma, Experimental
• Mice
• Mitochondria (metabolism)
• Mitochondrial Proteins (genetics, metabolism)
• Oxidation-Reduction
• Oxidative Phosphorylation
• Oxidative Stress
• Signal Transduction
• Uncoupling Protein 2