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Published on: June 9, 2023
Caveolin-1 regulates cancer cell metabolism via scavenging Nrf2 and suppressing MnSOD-driven glycolysis
Peter C Hart1,2, Bianca A Ratti1,3, Mao Mao1
1Department of Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.
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.
Insights
Caveolin-1 (Cav-1) suppresses Nrf2, which upregulates MnSOD and aerobic glycolysis in breast cancer. Loss of Cav-1 correlates with poor prognosis, offering a potential therapeutic target for cancer metabolism.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Aerobic glycolysis is a hallmark of aggressive cancer cells, distinguishing them from normal cells.
- Targeting cancer cell metabolism is a promising therapeutic strategy, but requires deeper understanding of metabolic reprogramming.
- MnSOD upregulation was previously identified as necessary and sufficient for glycolysis activation in breast cancer.
Purpose of the Study:
- To elucidate the molecular mechanisms driving MnSOD upregulation in breast cancer.
- To investigate the role of Caveolin-1 (Cav-1) in regulating MnSOD and glycolysis.
- To explore the clinical relevance of Cav-1 and MnSOD expression in invasive ductal carcinoma.
Main Methods:
- Investigated the interaction between Cav-1, Nrf2, and MnSOD in breast cancer cell lines (MCF10A(Er/Src) and MCF7).
- Assessed the impact of Cav-1 modulation on Nrf2 activation, MnSOD expression, and glycolytic rate.
- Utilized epidemiologic nested case-control studies to analyze Cav-1 and MnSOD expression in patient samples.
Main Results:
- Cav-1 suppresses Nrf2, a transcription factor upstream of MnSOD.
- Loss of Cav-1 leads to Nrf2 activation, MnSOD upregulation, and increased aerobic glycolysis dependent on mtH2O2 and AMPK.
- Restoring Cav-1 expression reduces Nrf2 and MnSOD levels.
- Epidemiologic studies show inverse Cav-1/MnSOD expression in invasive ductal carcinoma, with low Cav-1/high MnSOD linked to poorer survival and prognosis.
Conclusions:
- Cav-1 is a key regulator of MnSOD-driven aerobic glycolysis in breast cancer by suppressing Nrf2.
- The inverse relationship between Cav-1 and MnSOD expression in patients highlights their prognostic significance.
- Targeting the Cav-1/Nrf2/MnSOD axis represents a potential therapeutic strategy for aggressive breast cancer.
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