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.

Caveolin-1 controls mitochondrial function through regulation of m-AAA mitochondrial protease

“…This scenario is consistent with recent findings showing that a loss of caveolin-1 expression in breast cancer cells activates nuclear erythroid 2 p45-related factor-2 (Nrf2) and promotes manganese-dependent superoxide dismutase (MnSOD)-induced glycolysis and that reconstitution of caveolin-1 expression in caveolin-1-negative breast cancer cells suppresses Nrf2, reduces MnSOD expression, inhibits glycolysis and enhances mitochondria-dependent ATP production [41]. Interestingly, we have previously demonstrated that caveolin-1 is an endogenous inhibitor of Nrf2 and that Nrf2 is hyperactivated in caveolin-1 null MEFs [28].…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…The process is regulated by caveolin-1, which binds directly to both NRF2 and KEAP1, and impedes on NRF2 activation and hence on the glycolytic shift. This is apparently one explanation why glycolytic tumors, which are generally more aggressive, have a caveolin-1 low /Mn-superoxide dismutase high phenotype (Hart et al, 2016). NRF2 can also drive glucose and glutamine toward anabolic pathways required for tumor cell proliferation (Mitsuishi et al, 2012).…”

Caveolin-1 in the regulation of cell metabolism: a cancer perspective

“…In invasive ductal carcinoma, CAV1 is reduced at the early stage of progression and predicts poor survival outcome. Mechanistically, reduced CAV1 expression enabled the induction of transcription factor NRF2 (NF-E2-related factor 2), which activates anti-oxidant manganese superoxide dismutase (MnSOD) that triggers AMPK-dependent glycolysis [56]. As a proof, ectopic expression of CAV1 in invasive ductal carcinoma cells (MCF7) suppressed NRF2 expression, the induction of MnSOD, and decreased aerobic glycolytic phenotype as measured by extracellular acidification and lactate output [56].…”