Gomisin N: A herb-derived compound that enhances death receptormediated apoptosis of cancer cells

Tumor necrosis factor-α (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 heterodimer) signaling pathway. The kinase TAK1, a mitogen-activated protein kinase kinase kinase (MAP3K), has been widely accepted as a key kinase activating NF-κB and MAPKs in TNF-α signaling. We have recently reported that TAK1 regulates the transient phosphorylation and endocytosis of epidermal growth factor receptor (EGFR) in a tyrosine kinase activity-independent manner. Thr-669 and Ser-1046/7 were differently regulated via TAK1-ERK and TAK1-p38 pathways, respectively. In addition, p38, but not ERK, was involved in the endocytosis of EGFR. Surprisingly, modified EGFR was essential to prevent apoptotic cellular response: however, the EGFR was dependent of different signaling pathways, IκB kinase-NF-κB and MAPKs-EGFR, leading to the survival of cell exposed to the death signal from TNF-α receptor. We have recently screened gomisin N, a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra chinensis, that influenced death receptor-mediated apoptotic response. Gomisin N strongly promoted TNF-α-induced cleavage of caspase-3 and PARP-1, which are key markers of apoptosis. We found that gomisin N 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. Furthermore, gomisin N could protentiate TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through up-regulation of death receptore 4 (DR4) and DR5.The findings suggested that gomisin N migh be useful to promote death receptormediated apoptosis in the treatment of malignant tumor.