Caveolin‐1‐dependent regulation of cellular metabolism in breast cancer: role of Nrf‐2 and MnSOD (693.19)

Abstract

Caveolin‐1 (Cav‐1) is a plasma membrane associated protein that participates in the regulation of various signaling pathways affecting key cellular functions. According to our studies, variations in the expression levels of Cav‐1 heavily impact breast cancer cell metabolic adaptation that concurs with epidemiologic observations, indicating that Cav‐1 loss contributes to the glycolytic shift in advanced breast cancer. Mechanistically, we found that Cav‐1 ablation in breast cancer epithelial cells (MCF‐7) results in a marked increase in reactive oxygen species (ROS) production (e.g., 4 fold increase in H2O2) derived from MnSOD overexpression. Because MnSOD expression is downstream of Nrf‐2 nuclear factor, that is itself repressed by the association with Cav‐1, we hypothesize that loss of Cav‐1 leads to an increase in Nrf‐2‐dependent transcription and upregulation of MnSOD, which in turn activates AMPK by enhancing H2O2 outflow from mitochondria. In fact, cells devoid of Cav‐1 were shown to turn glycolytic in an H2O2‐ and AMPK‐dependent manner. Cav‐1 reconstitution or silencing of Nrf‐2 dampened AMPK activation and restored mitochondrial polarization along with decreasing the glycolytic rate. Relevantly, cells obtained from breast cancer patients at different stages of the disease showed progressive loss of Cav‐1 parallel to the upregulation of MnSOD, Nrf2, activated AMPK and a strong shift towards a predominantly glycolytic metabolism. Additionally, immunofluorescent staining of breast cancer tissue as compared to healthy controls recapitulated these findings. In conclusion, we propose that Cav‐1 may serve a tumor suppressive role by imposing metabolic restrictions for cancer progression via repressing Nrf2, MnSOD and ROS‐induced AMPK activation.Grant Funding Source: Supported by Dept of Defense (W911NF‐07‐R‐0003‐04), T32 Training Grant (T32HL072742‐09)