title: Caveolin-1 regulates cancer cell metabolism via scavenging Nrf2 and suppressing MnSOD-driven glycolysis.
abstract: Aerobic glycolysis is an indispensable component of aggressive cancer cell metabolism. It also distinguishes cancer cells from most healthy cell types in the body. Particularly for this reason, targeting the metabolism to improve treatment outcomes has long been perceived as a potentially valuable strategy. In practice, however, our limited knowledge of why and how metabolic reprogramming occurs has prevented progress towards therapeutic interventions that exploit the metabolic peculiarities of tumors. We recently described that in breast cancer, MnSOD upregulation is both necessary and sufficient to activate glycolysis. Here, we focused on determining the molecular mechanisms of MnSOD upregulation. We found that Caveolin-1 (Cav-1) is a central component of this mechanism due to its suppressive effects of NF-E2-related factor 2 (Nrf2), a transcription factor upstream of MnSOD. In transformed MCF10A(Er/Src) cells, Cav-1 loss preceded the activation of Nrf2 and its induction of MnSOD expression. Consistently, with previous observations, MnSOD expression secondary to Nrf2 activation led to an increase in the glycolytic rate dependent on mtH2O2 production and the activation of AMPK. Moreover, rescue of Cav-1 expression in a breast cancer cell line (MCF7) suppressed Nrf2 and reduced MnSOD expression. Experimental data were reinforced by epidemiologic nested case-control studies showing that Cav-1 and MnSOD are inversely expressed in cases of invasive ductal carcinoma, with low Cav-1 and high MnSOD expression being associated with lower 5-year survival rates and molecular subtypes with poorest prognosis.
authors.affiliation: Department of Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.|Department of Pathology, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hart
authors.affiliation: Department of Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.|Programa de Biociencias Aplicadas a Farmacia (PBF) Universidade Estadual de Maringa, Maringa, PR, Brazil.
authors.forename: Bianca A
authors.initials: BA
authors.lastname: Ratti
authors.affiliation: Department of Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Ansenberger-Fricano
authors.affiliation: Department of Oncology, Georgetown University, Medical Center, Washington, D.C., USA.
authors.forename: Ayesha N
authors.initials: AN
authors.lastname: Shajahan-Haq
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Tyner
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.|Department of Anesthesiology, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
authors.affiliation: Department of Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.|Department of Pathology, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.|Department of Pharmacology, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.|Programa de Biociencias Aplicadas a Farmacia (PBF) Universidade Estadual de Maringa, Maringa, PR, Brazil.
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Bonini
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D006019:Glycolysis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D061986:MCF-7 Cells; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011485:Protein Binding; D034622:RNA Interference; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D051242:Caveolin 1; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D013482:Superoxide Dismutase
keywords: Caveolin-1; MnSOD; Nrf2; breast cancer; tumor progression