Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Int J Oncol. 2012 Jan;40(1):203-8. doi: 10.3892/ijo.2011.1182. Epub 2011 Sep 1.
Tumor necrosis factor-alpha (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) are apoptosis-inducing ligands that stimulate death receptors. In this study, we investigated the effects of bufotalin, a major compound in toad venom, on sensitizing TNF-α and TRAIL-induced apoptosis of HeLa cells. Bufotalin promoted death receptor-mediated cell death, especially TRAIL-induced apoptosis, through activation of caspase-3 and PARP-1. Mitochondrial Bid-dependent pathway was activated in TNF-α-induced cell death. Cotreatment of bufotalin with TRAIL resulted in the downregulation of anti-apoptotic proteins, including Bcl-XL, Mcl-1, survivin and XIAP, and the up-regulation of MAPKs and TRAIL receptor DR5. In addition, phosphorylation of STAT1 was strongly inhibited by bufotalin. Moreover, DR5 expression was induced by knocking down the STAT1 expression. Moreover, the TRAIL-induced apoptotic response was promoted by STAT1 siRNA. Our results demonstrated that bufotalin is a powerful sensitizer of death receptor-induced apoptosis in cancer cells.
肿瘤坏死因子-α（TNF-α）和 TNF 相关凋亡诱导配体（TRAIL）是诱导凋亡的配体，可刺激死亡受体。在这项研究中，我们研究了蟾酥中主要化合物蟾毒它灵对 TNF-α和 TRAIL 诱导的 HeLa 细胞凋亡的增敏作用。蟾毒它灵通过激活 caspase-3 和 PARP-1 促进了死亡受体介导的细胞死亡，特别是 TRAIL 诱导的凋亡。TNF-α诱导的细胞死亡中激活了线粒体 Bid 依赖性途径。蟾毒它灵与 TRAIL 共同处理导致抗凋亡蛋白（包括 Bcl-XL、Mcl-1、survivin 和 XIAP）下调，并导致 MAPKs 和 TRAIL 受体 DR5 上调。此外，STAT1 的磷酸化被蟾毒它灵强烈抑制。此外，敲低 STAT1 表达可诱导 DR5 表达。此外，STAT1 siRNA 促进了 TRAIL 诱导的凋亡反应。我们的结果表明，蟾毒它灵是癌细胞中死亡受体诱导凋亡的有效增敏剂。
