Ye Changxiao, Zhao Wei, Li Minghui, Zhuang Junlong, Yan Xiang, Lu Qun, Chang Cunjie, Huang Xiaojing, Zhou Ji, Xie Bingxian, Zhang Zhen, Yao Xin, Yan Jun, Guo Hongqian
Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China; Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
PLoS One. 2015 Apr 7;10(4):e0122712. doi: 10.1371/journal.pone.0122712. eCollection 2015.
Vitamin E intake has been implicated in reduction of bladder cancer risk. However, the mechanisms remain elusive. Here we reported that δ-tocotrienol (δ-T3), one of vitamin E isomers, possessed the most potent cytotoxic capacity against human bladder cancer cells, compared with other Vitamin E isomers. δ-T3 inhibited cancer cell proliferation and colonogenicity through induction of G1 phase arrest and apoptosis. Western blotting assay revealed that δ-T3 increased the expression levels of cell cycle inhibitors (p21, p27), pro-apoptotic protein (Bax) and suppressed expression levels of cell cycle protein (Cyclin D1), anti-apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1), resulting in the Caspase-3 activation and cleavage of PARP. Moreover, the δ-T3 treatment inhibited ETK phosphorylation level and induced SHP-1 expression, which was correlated with downregulation of STAT3 activation. In line with this, δ-T3 reduced the STAT3 protein level in nuclear fraction, as well as its transcription activity. Knockdown of SHP-1 partially reversed δ-T3-induced cell growth arrest. Importantly, low dose of δ-T3 sensitized Gemcitabine-induced cytotoxic effects on human bladder cancer cells. Overall, our findings demonstrated, for the first time, the cytotoxic effects of δ-T3 on bladder cancer cells and suggest that δ-T3 might be a promising chemosensitization reagent for Gemcitabine in bladder cancer treatment.
维生素E的摄入与膀胱癌风险的降低有关。然而，其机制仍不清楚。在此我们报告，与其他维生素E异构体相比，维生素E异构体之一的δ-生育三烯酚（δ-T3）对人膀胱癌细胞具有最强的细胞毒性。δ-T3通过诱导G1期阻滞和凋亡来抑制癌细胞增殖和集落形成。蛋白质印迹分析显示，δ-T3增加细胞周期抑制剂（p21、p27）、促凋亡蛋白（Bax）的表达水平，并抑制细胞周期蛋白（细胞周期蛋白D1）、抗凋亡蛋白（Bcl-2、Bcl-xL和Mcl-1）的表达水平，导致半胱天冬酶-3激活和聚（ADP-核糖）聚合酶的裂解。此外，δ-T3处理抑制ETK磷酸化水平并诱导SHP-1表达，这与STAT3激活的下调相关。与此一致的是，δ-T3降低了细胞核部分的STAT3蛋白水平及其转录活性。敲低SHP-1部分逆转了δ-T3诱导的细胞生长停滞。重要的是，低剂量的δ-T3增强了吉西他滨对人膀胱癌细胞的细胞毒性作用。总体而言，我们的研究结果首次证明了δ-T3对膀胱癌细胞的细胞毒性作用，并表明δ-T3可能是吉西他滨在膀胱癌治疗中一种有前景的化学增敏试剂。
