Gomisin N enhances TNF-α-induced apoptosis via inhibition of the NF-κB and EGFR survival pathways
Tumor necrosis factor (TNF-α) is a pleiotropic cytokine that plays an important role in the control of cell proliferation, differentiation, and apoptosis. TNF-α-induced apoptosis is limited by TAK1-mediated activation of NF-κB (mainly p65-p50 hetrodimer) signaling pathway. We have recently reported that TAK1 regulates phosphorylation of EGFR at Ser-1046/7 through p38 MAPK, which cooperates with NF-κB in TNF-α-induced apoptosis. The present study investigated the effect of gomisins A and N, dibenzocyclooctadiene lignans isolated from the fruit of Schisandra chinensis, on TNF-α-induced apoptosis in HeLa cells. Gomisins A and N strongly promoted TNF-α-induced cleavage of caspase-3 and PARP-1, which are key markers of apoptosis. We found that gomisin N, but not gomisin A, inhibited the TNF-α-induced activation of NF-κB by suppressing the activation of IKKα. Gomisin N also inhibited p38-mediated phosphorylation of the EGFR at Ser-1046/7 and subsequent endocytosis of EGFR, another prosurvival pathway. The findings suggested that gomisin N enhanced TNF-α-induced apoptosis by suppressing of NF-κB and EGFR signaling pathways.
KeywordsTNF-α NF-κB EGFR Apoptosis Gomisin Schisandra chinensis
This work was supported in part by Grants-in-Aid for Challenging Exploratory Research (No. 09002374) and for the Knowledge Custer Initiative Toyama/Ishikawa Region (Hokuriku Innovation Cluster for Health Science) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, and a grant from the First Bank of Toyama Foundation.
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