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Methyl jasmonate sensitizes human bladder cancer cells to gambogic acid‐induced apoptosis through down‐regulation of EZH 2 expression by miR ‐101

2013; Wiley; Volume: 171; Issue: 3 Linguagem: Inglês

10.1111/bph.12501

1476-5381

Yongjun Wang, Wei Xiang, Miao Wang, Tao Huang, Xingyuan Xiao, Liang Wang, Dan Tao, Liyun Dong, Fuqing Zeng, Guosong Jiang,

Carbohydrate Chemistry and Synthesis

Background and Purpose Gambogic acid ( GA ) and methyl jasmonate ( MJ ) are increasingly being recognized as novel natural anticancer compounds. Here, we investigated the antitumour effects of GA in combination with MJ on human bladder cancer cells. Experimental Approach Cell viability was detected by cell counting kit‐8 assay. Cell apoptosis was assessed by H oechst 33258 staining and flow cytometry. Protein levels were determined by immunoblotting and expressions of mRNA and miRNAs by RT‐PCR . Differential expressions of a group of downstream genes were identified using microarray analysis. Key Results MJ significantly sensitized bladder cancer cells to GA ‐induced growth inhibition and apoptosis while sparing normal fibroblasts. MJ enhanced GA ‐induced activation of caspase‐3 and caspase‐9, and down‐regulated the expression of X IAP. Furthermore, treatment of bladder cancer cells with a combination of GA and MJ induced synergistic inhibition of the enhancer of zeste homologue 2 ( EZH 2) expression, whereas miR ‐101 expression was up‐regulated. Conversely, knockdown of miR ‐101 restored this decreased expression of EZH 2 and suppressed the inhibitory effect of GA and MJ on the growth of bladder cancer cells. Microarray analysis showed that genes closely associated with bladder cancer development were significantly down‐regulated by GA and MJ. In a s.c. xenograft mouse model of human bladder carcinoma, the combination of GA and MJ exerted an increased antitumour effect compared with GA alone. Conclusion and Implications MJ sensitizes bladder cancer cells to GA ‐induced apoptosis by down‐regulating the expression of EZH 2 induced by miR ‐101. Thus, the combination of selective anti‐cancer agents MJ and GA could provide a novel strategy for treating human bladder cancer.