Involvement of c-Src kinase in the regulation of TGF-beta1-induced apoptosis

• Published in: Oncogene Vol. 23; no. 37; pp. 6272 - 6281
• Main Authors: Park, Seok Soon, Eom, Young-Woo, Kim, Eun Hee, Lee, Ji Hyun, Min, Do Sik, Kim, Sungsub, Kim, Seong-Jin, Choi, Kyeong Sook
• Format: Journal Article
• Language: English
• Published: England 19.08.2004
• Subjects: Animals; Apoptosis - physiology; Blotting, Western; Caspases - metabolism; Cell Line, Tumor; CSK Tyrosine-Protein Kinase; DNA-Binding Proteins - metabolism; Enzyme Activation; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Phosphorylation; Protein-Tyrosine Kinases - metabolism; Protein-Tyrosine Kinases - physiology; Rats; Smad2 Protein; Smad3 Protein; src-Family Kinases; Subcellular Fractions - enzymology; Trans-Activators - metabolism; Transforming Growth Factor beta - physiology; Transforming Growth Factor beta1
• ISSN: 0950-9232

Transforming growth factor-beta1 (TGF-beta1) is a potent inducer of apoptosis in normal hepatocytes, and acquiring resistance to TGF-beta1 may be a critical step in the development of hepatocellular carcinoma (HCC). In this study, we investigated the possible involvement of c-Src in the regulation of TGF-beta1-induced apoptosis. TGF-beta1 induced transient activation of c-Src and its subsequent caspase-mediated degradation concomitant with cell death in FaO hepatoma cells, which are sensitive to TGF-beta1. In response to TGF-beta1, activated c-Src was translocated into the cytoplasmic membrane, then relocated to the nuclei of apoptotic cells during its cleavage. In TGF-beta1-induced apoptotic cells, c-Src maintained its tight association with p85 FAK fragment cleaved by caspases, possibly contributing to focal adhesion disassembly. TGF-beta1-induced apoptosis was enhanced by either inhibition of c-Src activity using PP1 or PP2, or by overexpression of dominant-negative c-Src. In contrast, overexpression of constitutively active c-Src inhibited apoptosis suppressing TGF-beta1-induced activation of p38, JNK and caspases. In many HCC cell lines resistant to TGF-beta1, enhanced c-Src activity was detected. We hypothesize that activated c-Src in HCC may contribute to resistance against the apoptotic and/ or antiproliferative properties of TGF-beta1.