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Smad7 Sensitizes Tumor Necrosis Factor–Induced Apoptosis through the Inhibition of Antiapoptotic Gene Expression by Suppressing Activation of the Nuclear Factor-B Pathway

¹ Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland and ² Laboratory of Cell Regulation and Carcinogenesis, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea

Requests for reprints: Seong-Jin Kim, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Songdo, Incheon 406-840, Korea. Phone: 82-32-820-4990; E-mail: jasonsjkim{at}gachon.ac.kr or seong-jin.kim{at}case.edu.

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-ß (TGF-ß) 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-B (NF-B), the cell survival factor, is markedly decreased in Smad7-stable cells. Furthermore, the expression of antiapoptotic target genes of NF-B is significantly reduced in accordance with the level of Smad7. In addition, Smad7 mediates the inhibitory activity of TGF-ß on TNF-induced NF-B activation and the synergistic activity of TGF-ß 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-B target genes. [Cancer Res 2007;67(19):9577–83]