Zhao Xiang-Zhai, Wu Xiao-Hua
Department of Gynecology and Obstetrics, The Third Hospital of Hebei Medical University, Hebei 050051, People's Republic of China.
Department of Gynecology and Obstetrics, Hebei Medical University, Hebei 050017, People’s Republic of China.
Onco Targets Ther. 2018 Jun 21;11:3609-3617. doi: 10.2147/OTT.S165723. eCollection 2018.
Spindlactone A (SPL-A) is a novel small molecule inhibitor of TACC3 that selectively inhibits the nucleation of centrosome microtubules and induces mitotic arrest in ovarian cancer cells. SPL-A is derived from dicoumarol which inhibits the activity of NAD(P)H dehydrogenase quinone oxidoreductase 1 (NQO1). This study aimed to investigate the mechanism by which SPL-A enhances TRAIL-induced apoptosis in endometrial carcinoma cells.
Endometrial carcinoma cells were treated with SPL-A and/or TRAIL, and the apoptosis and protein expression in the treated cells were examined.
Combined treatment with SPL-A and TRAIL significantly induced apoptosis in various human endometrial carcinoma cells, but not in normal human endometrial stromal cells and endometrial epithelial cells. Notably, both NQO1 inhibitor ES936 and NQO1 siRNA enhanced TRAIL-induced apoptosis of endometrial carcinoma cells. Furthermore, SPL-A downregulated the expression of c-FLIP, Bcl-2, Bcl-xl, and Mcl-1, while increasing p53 expression.
In particular, luciferase assay showed that SPL-A inhibited Bcl-2 promoter activity, and p53 inhibitor PFT-α could reverse the effect of SPL-A on Bcl-2 expression. Moreover, Bcl-2 overexpression inhibited the apoptosis induced by SPL-A and TRAIL. Taken together, our results suggest that SPL-A sensitizes endometrial cancer cells to TRAIL-induced apoptosis via the regulation of apoptosis-related proteins and the inhibition of NQO1 activity.
纺锤内酯A（SPL-A）是一种新型的TACC3小分子抑制剂，可选择性抑制中心体微管的成核，并诱导卵巢癌细胞发生有丝分裂停滞。SPL-A源自双香豆素，后者可抑制NAD（P）H脱氢酶醌氧化还原酶1（NQO1）的活性。本研究旨在探讨SPL-A增强TRAIL诱导的子宫内膜癌细胞凋亡的机制。
用SPL-A和/或TRAIL处理子宫内膜癌细胞，并检测处理后细胞的凋亡情况和蛋白表达。
SPL-A与TRAIL联合处理可显著诱导多种人子宫内膜癌细胞凋亡，但对正常人子宫内膜基质细胞和子宫内膜上皮细胞无此作用。值得注意的是，NQO1抑制剂ES936和NQO1 siRNA均增强了TRAIL诱导的子宫内膜癌细胞凋亡。此外，SPL-A下调了c-FLIP、Bcl-2、Bcl-xl和Mcl-1的表达，同时增加了p53的表达。
特别是，荧光素酶检测显示SPL-A抑制Bcl-2启动子活性，p53抑制剂PFT-α可逆转SPL-A对Bcl-2表达的影响。此外，Bcl-2过表达抑制了SPL-A和TRAIL诱导的凋亡。综上所述，我们的结果表明，SPL-A通过调节凋亡相关蛋白和抑制NQO1活性，使子宫内膜癌细胞对TRAIL诱导的凋亡敏感。
