title: Gomisin N enhances TNF-α-induced apoptosis via inhibition of the NF-κB and EGFR survival pathways.
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.
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
authors.forename: Pornthip
authors.initials: P
authors.lastname: Waiwut
authors.forename: Myoung-Sook
authors.initials: MS
authors.lastname: Shin
authors.forename: Akiko
authors.initials: A
authors.lastname: Inujima
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
authors.forename: Keiichi
authors.initials: K
authors.lastname: Koizumi
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D034242:Cyclooctanes / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D011083:Polycyclic Compounds / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D034242:Cyclooctanes; D017705:Lignans; D016328:NF-kappa B; D011083:Polycyclic Compounds; D014409:Tumor Necrosis Factor-alpha; C015499:schizandrin B; C512478:EGFR protein, human; D066246:ErbB Receptors