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Involvement of c-Src kinase in the regulation of TGF-β1-induced apoptosis

Oncogene volume 23, pages 6272–6281 (2004)Cite this article

Abstract

Transforming growth factor-β1 (TGF-β1) is a potent inducer of apoptosis in normal hepatocytes, and acquiring resistance to TGF-β1 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-β1-induced apoptosis. TGF-β1 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-β1. In response to TGF-β1, activated c-Src was translocated into the cytoplasmic membrane, then relocated to the nuclei of apoptotic cells during its cleavage. In TGF-β1-induced apoptotic cells, c-Src maintained its tight association with p85 FAK fragment cleaved by caspases, possibly contributing to focal adhesion disassembly. TGF-β1-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-β1-induced activation of p38, JNK and caspases. In many HCC cell lines resistant to TGF-β1, 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-β1.

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Abbreviations

TGF-β1:

transforming growth factor-β1

HCC:

hepatocellular carcinoma

PBS:

phosphate-buffered saline

PAGE:

polyacrylamide gel electrophoresis

TUNEL:

terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling

SDS–PAGE:

sodium dodecyl sulfate/polyacrylamide gel electrophoresis

DN:

dominant negative

CA:

constitutively active

GFP:

green fluorescence protein

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Acknowledgements

We sincerely thank Dr Edward B Leof for providing antiphospho-Smad3 antibody. This work was supported by Korea Research Foundation Grant (KRF-2000-F00045).

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Author notes

  1. Seok Soon Park and Young-Woo Eom: Seok Soon Park and Young Woo Eom contributed equally to this work

Authors and Affiliations

  1. Institute for Medical Sciences, Ajou University School of Medicine, 5 Wonchon-Dong, Paldal-Gu, Suwon, 442-749, Korea

    Seok Soon Park, Young-Woo Eom, Eun Hee Kim, Ji Hyun Lee & Kyeong Sook Choi

  2. Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, Korea

    Do Sik Min

  3. LG Life Science, Daejeon, Korea

    Sungsub Kim

  4. Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD, USA

    Seong-Jin Kim

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  1. Seok Soon Park
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Correspondence to Kyeong Sook Choi.

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Park, S., Eom, YW., Kim, E. et al. Involvement of c-Src kinase in the regulation of TGF-β1-induced apoptosis. Oncogene 23, 6272–6281 (2004). https://doi.org/10.1038/sj.onc.1207856

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