Mitochondrial Dysfunction and the Glycolytic Switch Induced by Caveolin-1 Phosphorylation Promote Cancer Cell Migration, Invasion, and Metastasis

SIMPLE SUMMARY: Caveolin-1 (CAV1) is a membrane protein that has been attributed a dual role in cancer, acting at early stages as a tumor suppressor and in later stages of the disease as a promoter of metastasis. In the latter case, enhanced expression of CAV1 favors the malignant phenotype and correlates with a poorer prognosis of the patients. Bearing in mind that the reprogramming of energy metabolism is required in cancer cells to meet both the bioenergetic and biosynthetic needs to sustain increased proliferation, migration, and invasion, we evaluated the metabolism of metastatic cells expressing or not CAV1. In this study, we show that the expression of CAV1 promotes in cancer cells a metabolic switch to an aerobic, glycolytic phenotype by blocking mitochondrial respiration. ABSTRACT: Cancer cells often display impaired mitochondrial function, reduced oxidative phosphorylation, and augmented aerobic glycolysis (Warburg effect) to fulfill their bioenergetic and biosynthetic needs. Caveolin-1 (CAV1) is a scaffolding protein that promotes cancer cell migration, invasion, and metastasis in a manner dependent on CAV1 phosphorylation on tyrosine-14 (pY14). Here, we show that CAV1 expression increased glycolysis rates, while mitochondrial respiration was reduced by inhibition of the mitochondrial complex IV. These effects correlated with increased reactive oxygen species (ROS) levels that favored CAV1-induced migration and invasion. Interestingly, pY14-CAV1 promoted the metabolic switch associated with increased migration/invasion and augmented ROS-inhibited PTP1B, a phosphatase that controls pY14 levels. Finally, the glycolysis inhibitor 2-deoxy-D-glucose reduced CAV1-enhanced migration in vitro and metastasis in vivo of murine melanoma cells. In conclusion, CAV1 promotes the Warburg effect and ROS production, which inhibits PTP1B to augment CAV1 phosphorylation on tyrosine-14, thereby increasing the metastatic potential of cancer cells.