Activation of a caspase-dependent oxidative damage response mediates TGFβ1 apoptosis in rat hepatocytes

Activation of transforming growth factor-β type 1- (TGFβ1) mediated signaling occurs in response to cell injury affecting stem-type cells and hepatocytes in liver. In this work we used WB stemlike liver epithelial cells and p53-defective CWSV-1 nontumorigenic rat hepatocytes to investigate the possible roles of caspases and oxidative stress in TGFβ1 signaling. TGFβ1 significantly increased the level of 4-hydroxy-2-nonenal (4-HNE), a stable product of lipid peroxidation. In addition, TGFβ1-treated cells exhibited activation of caspases that accompanied by enhanced cleavage of the caspase substrate poly(ADP)-ribose polymerase (PARP) and induction of apoptosis. WB cells were twice as sensitive as sensitive as CWSV-1 cells to induction of TGFβ1 apoptosis. TGFβ1-apoptosis was significantly reduced when cells were treated with TGFβ1 in the presence of inhibitors of caspase-1, -3, -8, and -9. Importantly, in addition to suppression of apoptosis, treatment of cells with the caspase-3 inhibitor Z-DEVD-FMK in the presence of TGFβ1 suppressed the formation 4-HNE and restored mitotic activity. Together, these data suggest TGFβ1 induces activation of a caspase signaling cascade that includes an oxidative damage response, PARP cleavage, and apoptosis that do not require intact p53 in rat hepatocytes.