Abstract
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.
Highlights
Protein phosphorylation, which is dynamic post-translational modification, can modify the protein function[12]
The KEGG analysis found that a variety of signaling pathways such as AMPK, mTOR and PI3K/Akt, which may regulate the stemness of pancreatic cancer cells, were enriched after gemcitabine exposure
We identified the phosphorylated proteins and signaling pathways relevant to the acquired stemness induced by low dose gemcitabine in pancreatic cancer cells by LC-MS/MS
Summary
Protein phosphorylation, which is dynamic post-translational modification, can modify the protein function[12]. It was known that phosphorylated proteins had specific molecular functions and some signaling pathways were differentially regulated through using reversible phosphorylation status of their constituent proteins[18] This information could be used to explain how the kinase network contributed to the different phenotypic characteristics of tumors, such as metastatic potential, stemness and chemosensitivity. The purpose of this study was to investigate the mechanisms underlying the acquired stemness in pancreatic cancer cells after gemcitabine treatment by detecting the phosphorylated proteins using iTRAQ analysis. The KEGG analysis found that a variety of signaling pathways such as AMPK, mTOR and PI3K/Akt, which may regulate the stemness of pancreatic cancer cells, were enriched after gemcitabine exposure. These results elucidated the potential mechanisms of acquired stemness in pancreatic cancer cells after gemcitabine treatment and determined potential targets for future intervention to improve the chemosensivity and prognosis of pancreatic cancer patients
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