Mitochondrial retrograde signaling mediated by UCP2 inhibits cancer cell proliferation and tumorigenesis.
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' Affiliations: Inserm, U1016, Institut Cochin; CNRS, UMR 8104; Université Paris Descartes, Sorbonne Paris Cité, Paris;
Pauline
P
Esteves
CRCNA-UMR 892 INSERM-6299 CNRS; and Faculté de Médecine, Université de Nantes, Nantes, France.
Claire
C
Pecqueur
Authors' Affiliations: Inserm, U1016, Institut Cochin; CNRS, UMR 8104; Université Paris Descartes, Sorbonne Paris Cité, Paris;
Céline
C
Ransy
Authors' Affiliations: Inserm, U1016, Institut Cochin; CNRS, UMR 8104; Université Paris Descartes, Sorbonne Paris Cité, Paris;
Catherine
C
Esnous
Authors' Affiliations: Inserm, U1016, Institut Cochin; CNRS, UMR 8104; Université Paris Descartes, Sorbonne Paris Cité, Paris;
Véronique
V
Lenoir
Authors' Affiliations: Inserm, U1016, Institut Cochin; CNRS, UMR 8104; Université Paris Descartes, Sorbonne Paris Cité, Paris;
Frédéric
F
Bouillaud
Authors' Affiliations: Inserm, U1016, Institut Cochin; CNRS, UMR 8104; Université Paris Descartes, Sorbonne Paris Cité, Paris;
Anne-Laure
AL
Bulteau
Authors' Affiliations: Inserm, U1016, Institut Cochin; CNRS, UMR 8104; Université Paris Descartes, Sorbonne Paris Cité, Paris;
Anne
A
Lombès
Authors' Affiliations: Inserm, U1016, Institut Cochin; CNRS, UMR 8104; Université Paris Descartes, Sorbonne Paris Cité, Paris;
Carina
C
Prip-Buus
Authors' Affiliations: Inserm, U1016, Institut Cochin; CNRS, UMR 8104; Université Paris Descartes, Sorbonne Paris Cité, Paris;
Daniel
D
Ricquier
Authors' Affiliations: Inserm, U1016, Institut Cochin; CNRS, UMR 8104; Université Paris Descartes, Sorbonne Paris Cité, Paris; clotilde.alves-guerra@inserm.fr.
Marie-Clotilde
MC
Alves-Guerra
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008546:Melanoma, Experimental; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D015398:Signal Transduction; D000071246:Uncoupling Protein 2
D051793:Hypoxia-Inducible Factor 1; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D055372:AMP-Activated Protein Kinases