Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin.
Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin.
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DOI：
10.1038/sj.bjc.6605285
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发表时间：
2009-10-06
影响因子：
8.8
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中科院分区：
文献类型：
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胰腺癌成功治疗的一个主要障碍是对现有化疗药物产生耐药性。吉西他滨是晚期和转移性胰腺癌的标准一线化疗药物，其耐药性主要归因于胰腺癌中细胞凋亡阈值的改变。MUC4跨膜糖蛋白在胰腺癌中异常过表达，并且最近已显示通过抑制细胞凋亡来增加胰腺肿瘤细胞生长。通过Annexin-V染色、DNA片段化分析、线粒体细胞色素c释放评估、免疫印迹和免疫共沉淀技术，在MUC4表达和MUC4敲除的胰腺癌细胞系中研究了MUC4对胰腺癌细胞对吉西他滨的耐药性的影响。Annexin-V染色和DNA片段化实验表明MUC4对吉西他滨诱导的CD18/HPAF胰腺癌细胞凋亡具有保护作用。与这些结果一致，MUC4也减弱了线粒体细胞色素c的释放和半胱天冬酶-9的活化。此外，我们的研究结果表明，MUC4通过HER2/细胞外信号调节激酶依赖性磷酸化和促凋亡蛋白Bad的失活发挥抗凋亡功能。我们的研究结果阐明了MUC4通过激活抗凋亡途径，从而促进细胞存活，从而赋予胰腺癌细胞对吉西他滨的抗性的功能。
A major obstacle to the successful management of pancreatic cancer is to acquire resistance to the existing chemotherapeutic agents. Resistance to gemcitabine, the standard first-line chemotherapeutic agent for advanced and metastatic pancreatic cancer, is mainly attributed to an altered apoptotic threshold in the pancreatic cancer. The MUC4 transmembrane glycoprotein is aberrantly overexpressed in the pancreatic cancer and recently, has been shown to increase pancreatic tumour cell growth by the inhibition of apoptosis. Effect of MUC4 on pancreatic cancer cells resistance to gemcitabine was studied in MUC4-expressing and MUC4-knocked down pancreatic cancer cell lines after treatment with gemcitabine by Annexin-V staining, DNA fragmentation assay, assessment of mitochondrial cytochrome c release, immunoblotting and co-immunoprecipitation techniques. Annexin-V staining and DNA fragmentation experiment demonstrated that MUC4 protects CD18/HPAF pancreatic cancer cells from gemcitabine-induced apoptosis. In concert with these results, MUC4 also attenuated mitochondrial cytochrome c release and the activation of caspase-9. Further, our results showed that MUC4 exerts anti-apoptotic function through HER2/extracellular signal-regulated kinase-dependent phosphorylation and inactivation of the pro-apoptotic protein Bad. Our results elucidate the function of MUC4 in imparting resistance to pancreatic cancer cells against gemcitabine through the activation of anti-apoptotic pathways and, thereby, promoting cell survival.