Du Juan, Wu Jinfeng, Fu Xiuqiong, Tse Anfernee Kai-Wing, Li Ting, Su Tao, Yu Zhi-Ling
Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
Department of Chinese Medicine, Changhai Hospital, The Second Military Medicine University, Shanghai, China.
Oncotarget. 2016 Aug 9;7(32):52218-52229. doi: 10.18632/oncotarget.10582.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, many melanoma cells show weak responses to TRAIL. Here, we investigated whether Icariside II (IS), an active component of Herba Epimedii, could potentiate antitumor effects of TRAIL in melanoma cells. Melanoma cells were treated with IS and/or TRAIL and cell death, apoptosis and signal transduction were analyzed. We showed that IS promoted TRAIL-induced cell death and apoptosis in A375 melanoma cells. Mechanistically, IS reduced the expression levels of cFLIP in a phospho-STAT3 (pSTAT3)-dependent manner. Ectopic expression of STAT3 abolished IS-induced cFLIP down-regulation and the associated potentiation of TRAIL-mediated cell death. Moreover, IS-induced reactive oxygen species (ROS) production preceded down-regulation of pSTAT3/cFLIP via activating AKT, and the consequent sensitization of cells to TRAIL. We also found that IS treatment down-regulated cFLIP via ROS-mediated NF-κB pathway. In addition, IS converted TRAIL-resistant melanoma MeWo and SK-MEL-28 cells into TRAIL-sensitive cells. Taken together, our results indicated that IS potentiated TRAIL-induced apoptosis through ROS-mediated down-regulation of STAT3/cFLIP signaling.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种很有前景的抗肿瘤药物。然而，许多黑色素瘤细胞对TRAIL反应较弱。在此，我们研究了淫羊藿活性成分淫羊藿苷II（IS）是否能增强TRAIL对黑色素瘤细胞的抗肿瘤作用。用IS和/或TRAIL处理黑色素瘤细胞，并分析细胞死亡、凋亡及信号转导情况。我们发现IS可促进TRAIL诱导的A375黑色素瘤细胞死亡和凋亡。机制上，IS以磷酸化信号转导和转录激活因子3（pSTAT3）依赖的方式降低细胞FLICE样抑制蛋白（cFLIP）的表达水平。STAT3的异位表达消除了IS诱导的cFLIP下调及TRAIL介导的细胞死亡增强作用。此外，IS诱导的活性氧（ROS）生成先于通过激活AKT导致的pSTAT3/cFLIP下调以及随后细胞对TRAIL的致敏。我们还发现IS处理通过ROS介导的核因子κB（NF-κB）途径下调cFLIP。另外，IS将对TRAIL耐药的黑色素瘤MeWo和SK-MEL-28细胞转化为对TRAIL敏感的细胞。综上所述，我们的结果表明IS通过ROS介导的STAT3/cFLIP信号下调增强了TRAIL诱导的凋亡。
