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Crosstalk between caveolae and the actin cytoskeleton via filamin a : implications for tumor cell migration and cancer progression

Cancer initiation and progression is a complex multistep process. Whereas initial steps in cell transformation by activation of oncogenes and inactivation of tumor suppressor proteins are well understood, subsequent cancer progression may involve additional proteins that mediate the acquisition of advanced-stage phenotypes. Caveolin-1 is an essential constituent of plasma membrane caveolae. However, caveolin-1 also negatively regulates mitogenic signaling and its genetic disruption sensitizes normal cells to oncogeneand carcinogen-induced tumorigenesis. These data have led to the suggestion that caveolin-1 acts as a tumor suppressor. However, recent results indicate that caveolin-1 is up-regulated in advanced-stage metastatic and multidrug resistant cancer cells, and that it promotes cancer cell survival under stress conditions. We have shown that caveolin-1 inhibits detachment-induced apoptosis through up-regulation of IGF-I receptor expression and signaling. In addition, heterologous expression of caveolin-1 stimulates cancer cell migration, while RNAi-mediated suppression of endogenous caveolin-1 attenuates this process. Caveolin-1 expression up-regulates the level and phosphorylation of the actin cross-linking protein filamin A. Filamin A is phosphorylated on Ser-2152, a site known to mediate enhanced cell migration and membrane ruffling, and is dependent on the PI3K/Akt pathway. Indeed, caveolin-1 co-exists in a complex with filamin A and the Akt kinase. Thus, the mechanism of caveolin1 action involves a physical and functional interaction with filamin A, through which caveolin-1 may regulate dynamic re-modeling of the actin cytoskeleton during cell migration. Caveolin-1 illustrates the critical role of accessory proteins in mediating enhanced cell survival, migration and invasion at late stages of cancer progression and highlights the long road to full understanding of cancer cell biology that still lies ahead.