Open Accessδ-Tocotrienol Induces Human Bladder Cancer Cell Growth Arrest, Apoptosis and Chemosensitization through Inhibition of STAT3 Pathway
Author(s) -
Changxiao Ye,
Wei Zhao,
Minghui Li,
Junlong Zhuang,
Yan Xiang,
Qun Lü,
Cunjie Chang,
Xiaojing Huang,
Ji Zhou,
Bingxian Xie,
Zhen Zhang,
Xin Yao,
Jun Yan,
Hongqian Guo
Publication year - 2015
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0122712
Subject(s) - apoptosis , cancer research , bladder cancer , cell cycle , cytotoxic t cell , cell cycle checkpoint , cell growth , cyclin d1 , cancer cell , chemistry , gene knockdown , g1 phase , downregulation and upregulation , stat3 , biology , cancer , medicine , biochemistry , gene , in vitro
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-x L 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.