Transforming growth factor-beta 1 induces apoptosis through Fas ligand-independent activation of the Fas death pathway in human gastric SNU-620 carcinoma cells.
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-beta 1 (TGF-beta 1)-induced apoptosis is not well understood. Herein, we report that apoptosis of human gastric SNU-620 carcinoma cells induced by TGF-beta 1 is caused by the Fas death pathway in a Fas ligand-independent manner, and that the Fas death pathway activated by TGF-beta 1 is linked to the mitochondrial apoptotic pathway via Bid mediation. We showed that TGF-beta 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-beta 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-beta 1. We further demonstrated that TGF-beta 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-beta 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-beta 1.
National Research Laboratory for Cancer Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea.
Sang Gyun
SG
Kim
Hyun-Soon
HS
Jong
Tae-You
TY
Kim
Jung Weon
JW
Lee
Noe Kyeong
NK
Kim
Seung Hwan
SH
Hong
Yung-Jue
YJ
Bang
D017209:Apoptosis / Q000187:drug effects*; D029681:Arabidopsis Proteins / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein; D002277:Carcinoma / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D044943:Fatty Acid Desaturases / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000378:metabolism*; D051900:Smad3 Protein; D013274:Stomach Neoplasms / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism
D029681:Arabidopsis Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C508960:TGFB1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019014:fas Receptor; D045304:Cytochromes c; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; D020169:Caspases