Methyl jasmonate sensitizes human bladder cancer cells to gambogic acid‐induced apoptosis through down‐regulation of EZH2 expression by miR‐101

• DOI: 10.1111/bph.12501
• Publication Date: 2013-11-06T10:49:15Z
• Authors: Yongjun Wang; Wei Xiang; Miao Wang; Tao Huang; Xingyuan Xiao; Liang Wang; Dan Tao; Liyun Dong; Fuqing Zeng; Guosong Jiang
• Keywords: Male; 0301 basic medicine; 0303 health sciences; Polycomb Repressive Complex 2; Mice, Nude; Apoptosis; Drug Synergism; Cyclopentanes; Acetates; Middle Aged; Antineoplastic Agents, Phytogenic; Neoplasm Proteins; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; MicroRNAs; 03 medical and health sciences; 13. Climate action; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Animals; Humans; Enhancer of Zeste Homolog 2 Protein; Female; Oxylipins

Background and PurposeGambogic 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 ApproachCell viability was detected by cell counting kit‐8 assay. Cell apoptosis was assessed by Hoechst 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 ResultsMJ 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 XIAP. Furthermore, treatment of bladder cancer cells with a combination of GA and MJ induced synergistic inhibition of the enhancer of zeste homologue 2 (EZH2) expression, whereas miR‐101 expression was up‐regulated. Conversely, knockdown of miR‐101 restored this decreased expression of EZH2 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 ImplicationsMJ sensitizes bladder cancer cells to GA‐induced apoptosis by down‐regulating the expression of EZH2 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.