ABSTRACT
Transforming growth factor (TGF)-ß 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-ß can trigger apoptosis and epithelial-mesenchymal transition (EMT). Caveolin-1 is associated with progression of hepatocellular cancer and has been linked to TGF-ß signaling. This study aimed at elucidating whether Caveolin-1 regulates TGF-ß mediated hepatocyte fate. Knockdown of Caveolin-1 strongly reduced TGF-ß mediated AKT phosphorylation, thus sensitized primary murine hepatocytes for proapoptotic TGF-ß 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-ß, indicating an additional mechanism how Caveolin-1 primes hepatocytes for resistance to TGF-ß triggered apoptosis. On the molecular level, Caveolin-1 interfered with TGF-ß 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 1α1, E- and N-cadherin expression upon TGF-ß challenge and thus no effect on hepatocyte EMT. Hence, via affecting TGF-ß mediated non-Smad AKT signaling and regulation of pro- and antiapoptotic factors, Caveolin-1 is a crucial hepatocyte fate determinant for TGF-ß effects.
