Smad7 sensitizes tumor necrosis factor induced apoptosis through the inhibition of antiapoptotic gene expression by suppressing activation of the nuclear factor-kappaB pathway.
Although tumor necrosis factor (TNF) induces apoptosis and cell death in many tumor cells, some cancer cells are still resistant to the TNF-induced death signal. In this report, we showed that Smad7, an inhibitory Smad of transforming growth factor-beta (TGF-beta) signaling, can overcome the TNF resistance in human breast and gastric cancer cells. Overexpression of Smad7 induces the degradation of poly(ADP-ribose) polymerase and the activation of caspase cascade. Although c-Jun NH2-terminal kinase (JNK) signaling is involved in TNF-induced cell death, the expression of Smad7 does not synergize the activation of JNK. However, the activation of nuclear factor-kappaB (NF-kappaB), the cell survival factor, is markedly decreased in Smad7-stable cells. Furthermore, the expression of antiapoptotic target genes of NF-kappaB is significantly reduced in accordance with the level of Smad7. In addition, Smad7 mediates the inhibitory activity of TGF-beta on TNF-induced NF-kappaB activation and the synergistic activity of TGF-beta on TNF-induced apoptosis. These findings suggest that Smad7 sensitizes the tumor cells to TNF-induced apoptosis through the inhibition of expression of antiapoptotic NF-kappaB target genes.
Hong
Suntaek
S
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
Lee
Chan
C
Kim
Seong-Jin
SJ
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051906:Smad7 Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D016328:NF-kappa B; D034741:RNA, Small Interfering; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D048670:MAP Kinase Kinase 4