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A more recent version of this article appeared on February 1, 2004
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Submitted on April 3, 2003
Revised on September 17, 2003
Accepted on October 1, 2003
1 Induces Apoptosis through Fas Ligand-independent Activation of the Fas Death Pathway in Human Gastric SNU-620 Carcinoma Cells
1 National Research Laboratory for Cancer Epigenetics, Cancer Research Institute, Seoul National University College of Medicine; School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea
2 National Research Laboratory for Cancer Epigenetics, Cancer Research Institute, Seoul National University College of Medicine
3 National Research Laboratory for Cancer Epigenetics, Cancer Research Institute, Seoul National University College of Medicine; Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea
4 Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea
5 School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea
* Corresponding author. E-mail address: bangyj{at}plaza.snu.ac.kr.
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
(FasL)-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 on 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.
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