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J. Biol. Chem., Vol. 278, Issue 41, 39615-39624, October 10, 2003

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Selenite-induced Survival of HuH7 Hepatoma Cells Involves Activation of Focal Adhesion Kinase-Phosphatidylinositol 3-Kinase-Akt Pathway and Rac1^*

Yu-Chi Lee  , Yun-Chi Tang  ¶ ||, Yi-Hsien Chen  ¶, Chiuan-Mei Wong ¶ and Ann-Ping Tsou  ¶ **

From the Institute of Genetics, School of Life Sciences, National Yang-Ming University, Shih-Pai, Taipei 112, Taiwan, Republic of China and the ^¶Institute of Biotechnology in Medicine, School of Medical Technology and Engineering, National Yang-Ming University, Shih-Pai, Taipei 112, Taiwan, Republic of China

Selenium has been shown to sustain the growth of selected human hepatocellular carcinoma cell lines under serum-free conditions, but the detailed mechanism remained undetermined. In the present study, the molecular mechanism(s) involving sodium selenite (Na₂SO₃, Se) as a survival agent were determined. Selenite not only protects HuH7 cells from serum deprivation-induced apoptosis, it also supports its long-term growth in sodium selenite (10^–7 M) supplemented serum-free medium. The anti-apoptotic effect correlates with activation of focal adhesion kinase and the phosphatidylinositol 3-kinase (PI3K)-Akt kinase pathway. Using HuH7 cells stably transfected with a constitutively active Akt kinase and PI3K inhibitor LY294002, selenite-induced cell survival was shown to be PI3K-Akt-dependent. Parallel changes included a significant reduction in the intracellular reactive oxygen species content, the reversal of DNA fragmentation, and the suppression of caspase and apoptosis signal-regulating kinase 1 activities. HuH7 cells stably expressing a Rac1 mutant N17 (Rac1^N17-HuH7) are refractory to selenite treatment. In these cells selenite supplement neither triggers Akt activation nor supports cell proliferation. Participation of Rac1 activation in this event is supported by the fact that selenite treatment drastically enhanced activation of Rac1. The exact link between selenite treatment, Rac1 activation, and activation of the focal adhesion kinase-PI 3-kinase, however, remains to be characterized. The mitogenic signaling mediated by selenite may involve unconventional growth stimuli including higher glutathione peroxidase 1 activity and higher transcription levels of selenoprotein P. The selenium-HuH7 system we have established thus provides a unique tool that will allow the biological role of selenite in growth regulation of hepatocytes to be studied in detail.

Received for publication, April 18, 2003 , and in revised form, July 17, 2003.

^* This work was supported in part by National Science Council Grant 90-2314-B-010-050 (to A.-P. T.) and Veterans General Hospital-Taipei Grant V89-383 (to A.-P. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^|| Current address: Max-Planck-Institut of Biochemie, Department of Cellular Biochemistry Am Klopferspitz 18a, Germany.

^** To whom correspondence should be addressed: Institute of Biotechnology in Medicine, National Yang-Ming University, Shih-Pai, Taipei 112, Taiwan, Republic of China. Tel.: 886-2-2826-7155; Fax: 886-2-2826-4092; E-mail: aptsou{at}ym.edu.tw.

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