ST6Gal-I modulates docetaxel sensitivity in human hepatocarcinoma cells via the p38 MAPK/caspase pathway.
ST6Gal-I modulates docetaxel sensitivity in human hepatocarcinoma cells via the p38 MAPK/caspase pathway.
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DOI：
10.18632/oncotarget.10192
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发表时间：
2016-08-09
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
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作者：
Chen X;Wang L;Zhao Y;Yuan S;Wu Q;Zhu X;Niang B;Wang S;Zhang J
β-半乳糖苷α2-6-唾液酸转移酶1（ST 6 Gal-I）是负责将α2-6-唾液酸添加到细胞表面N-聚糖末端的主要唾液酸转移酶。尽管先前已报道了ST 6 Gal-I在癌细胞对化疗剂的耐药性中的作用，但ST 6 Gal-I在肝细胞癌（HCC）的临床耐药性中的作用尚不完全清楚。在这项研究中，我们发现，ST 6 Gal-I的敲低增加肝癌MHCC 97-H细胞多西他赛治疗的敏感性，通过煽动凋亡的过程。沉默ST 6 Gal-I表达可降低多西他赛处理后MHCC 97-H细胞的存活率。重要的是，ST 6 Gal-I沉默导致磷酸化p38、Bax、Bad、细胞色素c和切割的半胱天冬酶-9，3和PARP的增加，而抗凋亡蛋白Bcl-2的减少。此外，我们发现p38 MAPK和caspase-3抑制剂可以降低ST 6 Gal-I沉默或多西他赛处理导致的MHCC 97-H细胞凋亡水平的增加。相反，外源性ST 6 Gal-I在肝癌Huh 7细胞中的表达通过抑制p38 MAPK介导的细胞依赖性途径抑制凋亡细胞死亡并阻止紫杉醇诱导的凋亡。这些结果表明，ST 6 Gal-I可能在介导人肝癌细胞存活中发挥积极作用，并可能成为基因治疗和抗肿瘤药物治疗的潜在靶点。
The β-galactoside α2-6-sialyltransferase 1 (ST6Gal-I) is the principal sialyltransferase responsible for the addition of α2-6-sialic acid to the termini N-glycans on cell surface. Although ST6Gal-I in cancer cell resistance to chemotherapeutics agents has been previously reported, the role of ST6Gal-I in clinical drug resistance of hepatocellular carcinoma (HCC) is not fully understood. In this study, we found that knockdown of ST6Gal-I increased the sensitivity of hepatocarcinoma MHCC97-H cells to docetaxel treatment by instigating the process of apoptosis. Silencing ST6Gal-I expression decreased the survival rate of MHCC97-H cells after docetaxel treatment. Importantly, ST6Gal-I silencing resulted in an increasing of phospho-p38, Bax, Bad, cytochrome c and the cleaved caspase-9, 3 and PARP, while a decreasing of the anti-apoptotic protein Bcl-2. In addition, we found that p38 MAPK and caspase-3 inhibitors can reduce the enhanced apoptosis levels of MHCC97-H cells resulted by either ST6Gal-I silencing or docetaxel treatment. Conversely, exogenous expression of ST6Gal-I in hepatocarcinoma Huh7 cells inhibited apoptotic cell death and prevented docetaxel-induced apoptosis by inhibiting p38 MAPK mediated mitochondrial-dependent pathway. Taken together, these results indicate that ST6Gal-I might play a positive role in mediating the survival of human hepatocarcinoma cells and could be a potential target for gene and antitumor drugs therapy.