Mechanistic Evaluation and Translational Signature of Gemcitabine-induced Chemoresistance by Quantitative Phosphoproteomics Analysis with iTRAQ Labeling Mass Spectrometry
Mechanistic Evaluation and Translational Signature of Gemcitabine-induced Chemoresistance by Quantitative Phosphoproteomics Analysis with iTRAQ Labeling Mass Spectrometry
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使用 iTRAQ 标记质谱进行定量磷酸化蛋白质组学分析，对吉西他滨诱导的化疗耐药性进行机制评估和转化特征
DOI：
10.1038/s41598-017-13330-2
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发表时间：
2017-10-10
影响因子：
4.6
通讯作者：
Yin，Tao
中科院分区：
文献类型：
--
作者：
Duan，Qingke;Zhao，Hengqiang;Yin，Tao
缺乏有效的化疗是胰腺癌预后不良的主要原因之一。吉西他滨是一种广泛使用的化疗药物，但由于化疗耐药，其治疗效果有限。最近的研究表明，癌症干细胞的存在可能导致化疗失败。此外，吉西他滨可以促进胰腺癌细胞的干细胞性。我们利用iTRAQ标记LC-MS/MS检测了吉西他滨处理后胰腺癌细胞中蛋白质磷酸化和信号通路的变化，因为它具有分离能力强和分析范围广的优点。本研究共鉴定出 232 个差异表达的磷酸化蛋白。基因本体分析显示，核腔、核部分和细胞器腔富集了细胞成分，蛋白质结合、聚腺苷酸RNA结合和RNA结合富集了分子功能。基于KEGG分析丰富了多种信号通路。 AMPK、mTOR 和 PI3K/Akt 通路在吉西他滨暴露后得到验证。此外，我们发现基于 PPI 图谱，磷酸化蛋白在调节吉西他滨暴露诱导的癌症干性方面存在复杂的相互作用。我们的实验可能会确定使胰腺癌细胞对吉西他滨敏感的潜在靶点和策略。
One of the main causations of the poor prognosis of pancreatic cancer is the lack of effective chemotherapies. Gemcitabine is a widely used chemotherapeutic drug, but limited therapeutic efficacy is achieved due to chemoresistance. Recent studies demonstrated that the presence of cancer stem cells may lead to the failure of chemotherapy. Moreover, gemcitabine can promote the stemness of pancreatic cancer cells. We detected the alterations in protein phosphorylation and signaling pathways in pancreatic cancer cells after gemcitabine treatment using iTRAQ labeling LC-MS/MS, because it was featured with the advantages of strong separation ability and analysis range. A total of 232 differentially expressed phosphorylated proteins were identified in this study. Gene Ontology analysis revealed that nuclear lumen, nuclear part and organelle lumen were enriched for cell components and protein binding, poly (A) RNA binding and RNA binding were enriched for molecular function. A variety of signaling pathways were enriched based on KEGG analysis. AMPK, mTOR and PI3K/Akt pathways were verified after gemcitabine exposure. Moreover, we found there were complex interactions of phosphorylated proteins in modulating cancer stemness induced by gemcitabine exposure based on PPIs map. Our experiments may identify potential targets and strategies for sensitizing pancreatic cancer cells to gemcitabine.