title: δ-tocotrienol induces human bladder cancer cell growth arrest, apoptosis and chemosensitization through inhibition of STAT3 pathway.
abstract: 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.
authors: 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.
authors: Changxiao
authors: C
authors: Ye
authors: Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
authors: Wei
authors: W
authors: Zhao
authors: Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
authors: Minghui
authors: M
authors: Li
authors: Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
authors: Junlong
authors: J
authors: Zhuang
authors: Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
authors: Xiang
authors: X
authors: Yan
authors: Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
authors: Qun
authors: Q
authors: Lu
authors: Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
authors: Cunjie
authors: C
authors: Chang
authors: Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
authors: Xiaojing
authors: X
authors: Huang
authors: Department of Respiratory Medicine, The first affiliated hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors: Ji
authors: J
authors: Zhou
authors: Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
authors: Bingxian
authors: B
authors: Xie
authors: Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China.
authors: Zhen
authors: Z
authors: Zhang
authors: Department of Respiratory Medicine, The first affiliated hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors: Xin
authors: X
authors: Yao
authors: Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
authors: Jun
authors: J
authors: Yan
authors: Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China; Nanjing Urology Research Center, Nanjing, Jiangsu 210008, China.
authors: Hongqian
authors: H
authors: Guo
mesh_terms: D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D003841:Deoxycytidine; D014810:Vitamin E; C082097:tocotrienol, delta; C492367:BMX protein, human; D011505:Protein-Tyrosine Kinases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D000093542:Gemcitabine