Ibulocydine sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis via calpain-mediated Bax cleavage

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• 作者：Seok Soon Park^a ; ^b ; Eunjin Jwa^h ; Seol Hwa Shin^b ; Eun Jin Ju^b ; Intae Park^b ; Jhang Ho Pak^a ; ^d ; Jung Jin Hwang^a ; ^b ; ^c ; ^d ; Dong-Hyung Choⁱ ; B.Moon Kim^j ; Sung-Bae Kim^f ; Jung Shin Lee^a ; ^g ; Si Yeol Song^b ; ^c ; ^e ; ^{coocoori@amc.seoul.kr} ; Seong-Yun Jeong^a ; ^b ; ^c ; ^d ; ^{syj@amc.seoul.kr} ; Eun Kyung Choi^b ; ^c ; ^e ; ^{ekchoi@amc.seoul.kr}
• 关键词：Ibulocydine ; Mitochondria ; Cleaved-Bax ; Caspase ; Calpain
• 刊名：The International Journal of Biochemistry & Cell Biology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：83
• 期：Complete
• 页码：47-55
• 全文大小：2260 K
• 卷排序：83

文摘

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) induces apoptosis selectively in cancer cells without affecting the majority of normal human cells. However, hepatocellular carcinoma (HCC) cells often display resistance to TRAIL-induced apoptosis. Ibulocydine (IB) is an isobutyrate ester pro-drug of a novel synthetic Cdk inhibitor that targets Cdk7 and Cdk9. In this study, we show that treatment with subtoxic doses of IB in combination with TRAIL displays potent cytotoxicity in TRAIL-resistant human HCC cells. Combination of IB and TRAIL was found to synergistically induce apoptosis through activation of caspases, which was blocked by a pan-caspase inhibitor (zVAD). Although the expression of Mcl-1 and survivin were reduced by IB plus TRAIL, overexpression of Mcl-1 and survivin did not block the cell death induced by co-treatment. Moreover, overexpression of Bcl-xL did not significantly interfere with the cell death induced by co-treatment of IB and TRAIL. Interestingly, the combination treatment induced cleavage of Bax, which was translocated to mitochondria upon induction of apoptosis. Furthermore, down-regulation of Bax by small interfering RNA effectively reduced the cell death and loss of mitochondrial membrane potential (MMP) caused by co-treatment with IB and TRAIL. Finally, pre-treatment of HCC cells with a calpain inhibitor effectively blocked IB plus TRAIL-induced cleavage of Bax and apoptosis. Collectively, our results demonstrate that IB increases the sensitivity of human HCC cells to TRAIL via mitochondria signaling pathway mediated by calpain-induced cleavage of Bax, suggesting that combined treatment with IB and TRAIL may offer an effective therapeutic strategy for human HCC.