Involvement of c-Src kinase in the regulation of TGF- 1-induced apoptosis

• Published in: Oncogene Vol. 23; no. 37; pp. 6272 - 6281
• Main Authors: Park, Seok Soon, Young-Woo, Eom, Kim, Eun Hee, Lee, Ji Hyun, Min, Do Sik, Kim, Sungsub, Seong-Jin, Kim, Choi, Kyeong Sook
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 19.08.2004
• Subjects: Antibodies; Apoptosis; Cell death; Growth factors; Kinases; Liver cancer; Mutation; Proteins
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207856

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.