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Vol. 15, Issue 2, 420-434, February 2004

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Transforming Growth Factor-1 Induces Apoptosis through Fas Ligand-independent Activation of the Fas Death Pathway in Human Gastric SNU-620 Carcinoma Cells

Sang Gyun Kim ^* , Hyun-Soon Jong ^*, Tae-You Kim ^* , Jung Weon Lee ^*, Noe Kyeong Kim , Seung Hwan Hong , and Yung-Jue Bang ^*  

^* National Research Laboratory for Cancer Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea; and School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea

Submitted April 3, 2003; Revised September 17, 2003; Accepted October 1, 2003
Monitoring Editor: Carl-Henrik Heldin

To date, two major apoptotic pathways, the death receptor and the mitochondrial pathway, have been well documented in mammalian cells. However, the involvement of these two apoptotic pathways, particularly the death receptor pathway, in transforming growth factor-1 (TGF-1)-induced apoptosis is not well understood. Herein, we report that apoptosis of human gastric SNU-620 carcinoma cells induced by TGF-1 is caused by the Fas death pathway in a Fas ligand-independent manner, and that the Fas death pathway activated by TGF-1 is linked to the mitochondrial apoptotic pathway via Bid mediation. We showed that TGF-1 induced the expression and activation of Fas and the subsequent caspase-8-mediated Bid cleavage. Interestingly, expression of dominant negative FADD and treatment with caspase-8 inhibitor efficiently prevented TGF-1-induced apoptosis, whereas the treatment with an activating CH11 or a neutralizing ZB4 anti-Fas antibody, recombinant Fas ligand, or Fas-Fc chimera did not affect activation of Fas and the subsequent induction of apoptosis by TGF-1. We further demonstrated that TGF-1 also activates the mitochondrial pathway showing Bid-mediated loss of mitochondrial membrane potential and subsequent cytochrome c release associated with the activations of caspase-9 and the effector caspases. Moreover, all these apoptotic events induced by TGF-1 were found to be effectively inhibited by Smad3 knockdown and also completely abrogated by Smad7 expression, suggesting the involvement of the Smad3 pathway upstream of the Fas death pathway by TGF-1.

Corresponding author. E-mail address: bangyj{at}plaza.snu.ac.kr.

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