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Gomisin N enhances TNF-α-induced apoptosis via inhibition of the NF-κB and EGFR survival pathways

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Abstract

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.

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Acknowledgments

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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  1. Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Pornthip Waiwut, Myoung-Sook Shin, Akiko Inujima, Yue Zhou, Keiichi Koizumi, Ikuo Saiki & Hiroaki Sakurai

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  1. Pornthip Waiwut
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  2. Myoung-Sook Shin
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  3. Akiko Inujima
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  4. Yue Zhou
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  5. Keiichi Koizumi
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  6. Ikuo Saiki
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  7. Hiroaki Sakurai
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Correspondence to Hiroaki Sakurai.

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Waiwut, P., Shin, MS., Inujima, A. et al. Gomisin N enhances TNF-α-induced apoptosis via inhibition of the NF-κB and EGFR survival pathways. Mol Cell Biochem 350, 169–175 (2011). https://doi.org/10.1007/s11010-010-0695-z

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  • DOI: https://doi.org/10.1007/s11010-010-0695-z

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