Gomisin N enhances TNF-α-induced apoptosis via inhibition of the NF-κB and EGFR survival pathways
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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.
- 6.Marek J, Slanina J (1998) Gomisin N. Acta Cryst 54:1548–1550Google Scholar
- 7.Opletal L, Sovová H, Bártlová M (2004) Dibenzo[a,c]cyclooctadiene lignans of the genus Schisandra: importance, isolation and determination. J Chromatogr B 812:357–371Google Scholar
- 10.Yim SY, Lee YJ, Lee YK, Jung SE, Kim JH, Kim HJ, Son BG, Park YH, Lee YG, Choi YW, Hwang DY (2009) Gomisin N isolated from Schisandra chinensis significantly induces anti-proliferative and pro-apoptotic effects in hepatic carcinoma. Mol Med Rep 2:725–732Google Scholar
- 16.Nishimura M, Shin MS, Singhirunnusorn P, Suzuki S, Kawanishi M, Koizumi K, Saiki I, Sakurai H (2009) TAK1-mediated serine/threonine phosphorylation of epidermal growth factor receptor via p38/extracellular signal-regulated kinase: NF-κB-independent survival pathways in tumor necrosis factor alpha signaling. Mol Cell Biol 29:5529–5539PubMedCrossRefGoogle Scholar
- 18.Singhirunnusorn P, Suzuki S, Kawasaki N, Saiki I, Sakurai H (2005) Critical roles of threonine 187 phosphorylation in cellular stress-induced rapid and transient activation of transforming growth factor-β-activated kinase 1 (TAK1) in a signaling complex containing TAK. J Biol Chem 280:7359–7368PubMedCrossRefGoogle Scholar