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

Tumor necrosis factor (TNF-alpha) is a pleiotropic cytokine that plays an important role in the control of cell proliferation, differentiation, and apoptosis. TNF-alpha-induced apoptosis is limited by TAK1-mediated activation of NF-kappa B (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-kappa B in TNF-alpha-induced apoptosis. The present study investigated the effect of gomisins A and N, dibenzocyclooctadiene lignans isolated from the fruit of Schisandra chinensis, on TNF-alpha-induced apoptosis in HeLa cells. Gomisins A and N strongly promoted TNF-alpha-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-alpha-induced activation of NF-kappa B by suppressing the activation of IKK alpha. 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-alpha-induced apoptosis by suppressing of NF-kappa B and EGFR signaling pathways.