Caveolin-1 abrogates TGF-β mediated hepatocyte apoptosis

Transforming growth factor (TGF)-beta has a dual role in liver, providing cytostatic effects during liver damage and regeneration, as well as carcinogenic functions in malignant transformation and hepatocellular cancer. In cultured hepatocytes, TGF-beta can trigger apoptosis and epithelial-mesenchymal transition (EMT). Caveolin-1 is associated with progression of hepatocellular cancer and has been linked to TGF-beta signaling. This study aimed at elucidating whether Caveolin-1 regulates TGF-beta mediated hepatocyte fate. Knockdown of Caveolin-1 strongly reduced TGF-beta mediated AKT phosphorylation, thus sensitized primary murine hepatocytes for proapoptotic TGF-beta signaling. Restoration of AKT activity in Caveolin-1 knockdown cells via expression of a constitutive active AKT mutant did not completely blunt the apoptotic response to TGF-beta, indicating an additional mechanism how Caveolin-1 primes hepatocytes for resistance to TGF-beta triggered apoptosis. On the molecular level, Caveolin-1 interfered with TGF-beta initiated expression of the proapoptotic mediator BIM. Additionally, RNAi for Caveolin-1 reduced ( and its overexpression increased) expression of antiapoptotic mediators BCL-2 and BCL-xl. Noteworthy, reduced Caveolin-1 protein levels had no effect on collagen 1 alpha 1, E- and N-cadherin expression upon TGF-beta challenge and thus no effect on hepatocyte EMT. Hence, via affecting TGF-beta mediated non-Smad AKT signaling and regulation of pro- and antiapoptotic factors, Caveolin-1 is a crucial hepatocyte fate determinant for TGF-beta effects. Cell Death and Disease (2013) 4, e466; doi:10.1038/cddis.2012.204; published online 17 January 2013