Fukuda Tomohiko, Oda Katsutoshi, Wada-Hiraike Osamu, Sone Kenbun, Inaba Kanako, Ikeda Yuji, Makii Chinami, Miyasaka Aki, Kashiyama Tomoko, Tanikawa Michihiro, Arimoto Takahide, Yano Tetsu, Kawana Kei, Osuga Yutaka, Fujii Tomoyuki
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo 162-0052, Japan.
Oncol Lett. 2016 Oct;12(4):2560-2566. doi: 10.3892/ol.2016.4978. Epub 2016 Aug 8.
Resveratrol (RSV), a polyphenolic compound derived from red wine, inhibits the proliferation of various types of cancer. RSV induces apoptosis in cancer cells, while enhancing autophagy. Autophagy promotes cancer cell growth by driving cellular metabolism, which may counteract the effect of RSV. The present study aimed to elucidate the correlation between RSV and autophagy and to examine whether autophagy inhibition may enhance the antitumor effect of RSV in endometrial cancer cells. Cell proliferation, cell cycle progression and apoptosis were examined, following RSV exposure, by performing MTT assays, flow cytometry and annexin V staining, respectively, in an Ishikawa endometrial cancer cell line. Autophagy was evaluated by measuring the expression levels of light chain 3, II (LC3-II; an autophagy marker) by western blotting and immunofluorescence. Chloroquine (CQ) and small interfering RNAs targeting autophagy related (ATG) gene 5 () or 7 () were used to inhibit autophagy, and the effects in combination with RSV were assessed using MTT assays. RSV treatment suppressed cell proliferation in a dose-dependent manner in Ishikawa cells. In addition, RSV exposure increased the abundance of the sub-G1 population and induced apoptosis. LC3-II accumulation was observed following RSV treatment, indicating that RSV induced autophagy. Combination treatment with CQ and RSV more robustly suppressed growth inhibition and apoptosis, compared with RSV treatment alone. Knocking down or expression significantly augmented RSV-induced apoptosis. The results of the present study indicated that RSV-induced autophagy may counteract the antitumor effect of RSV in Ishikawa cells. Combination treatment with RSV and an autophagy inhibitor, such as CQ, may be an attractive therapeutic option for treating certain endometrial cancer cells.
白藜芦醇(RSV)是一种源自红酒的多酚类化合物,可抑制多种类型癌症的增殖。RSV诱导癌细胞凋亡,同时增强自噬。自噬通过驱动细胞代谢促进癌细胞生长,这可能抵消RSV的作用。本研究旨在阐明RSV与自噬之间的相关性,并研究自噬抑制是否可增强RSV对子宫内膜癌细胞的抗肿瘤作用。在石川子宫内膜癌细胞系中,分别通过MTT试验、流式细胞术和膜联蛋白V染色检测RSV处理后的细胞增殖、细胞周期进程和凋亡情况。通过蛋白质免疫印迹法和免疫荧光法检测轻链3 II型(LC3-II;一种自噬标志物)的表达水平来评估自噬。使用氯喹(CQ)和靶向自噬相关(ATG)基因5( )或7( )的小干扰RNA抑制自噬,并通过MTT试验评估其与RSV联合使用的效果。RSV处理以剂量依赖方式抑制石川细胞的增殖。此外,RSV处理增加了亚G1期细胞群体的丰度并诱导凋亡。RSV处理后观察到LC3-II积累,表明RSV诱导了自噬。与单独使用RSV处理相比,CQ和RSV联合处理更有力地抑制了生长并诱导了凋亡。敲低 或 的表达显著增强了RSV诱导的凋亡。本研究结果表明,RSV诱导的自噬可能抵消RSV对石川细胞的抗肿瘤作用。RSV与自噬抑制剂(如CQ)联合治疗可能是治疗某些子宫内膜癌细胞的有吸引力的治疗选择。