Dataset Information

Proteomic Analysis of Combined Gemcitabine and Birinapant in Pancreatic Cancer Cells.

ABSTRACT: Pancreatic cancer is characterized by mutated signaling pathways and a high incidence of drug resistance. Comprehensive, large-scale proteomic analysis can provide a system-wide view of signaling networks, assist in understanding drug mechanisms of action and interactions, and serve as a useful tool for pancreatic cancer research. In this study, liquid chromatography-mass spectrometry-based proteomic analysis was applied to characterize the combination of gemcitabine and birinapant in pancreatic cancer cells, which was shown previously to be synergistic. A total of 4069 drug-responsive proteins were identified and quantified in a time-series proteome analysis. This rich dataset provides broad views and accurate quantification of signaling pathways. Pathways relating to DNA damage response regulations, DNA repair, anti-apoptosis, pro-migration/invasion were implicated as underlying mechanisms for gemcitabine resistance and for the beneficial effects of the drug combination. Promising drug targets were identified for future investigation. This study also provides a database for systems mathematical modeling to relate drug effects and interactions in various signaling pathways in pancreatic cancer cells.

SUBMITTER: Zhu X

PROVIDER: S-EPMC5827530 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Proteomic Analysis of Combined Gemcitabine and Birinapant in Pancreatic Cancer Cells.

Zhu Xu X Shen Xiaomeng X Qu Jun J Straubinger Robert M RM Jusko William J WJ

Frontiers in pharmacology 20180219

Pancreatic cancer is characterized by mutated signaling pathways and a high incidence of drug resistance. Comprehensive, large-scale proteomic analysis can provide a system-wide view of signaling networks, assist in understanding drug mechanisms of action and interactions, and serve as a useful tool for pancreatic cancer research. In this study, liquid chromatography-mass spectrometry-based proteomic analysis was applied to characterize the combination of gemcitabine and birinapant in pancreatic ...[more]

PMID: 29520231

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Project description:Despite decades of effort, pancreatic adenocarcinoma (PDAC) remains an intractable clinical challenge. An insufficient understanding of mechanisms underlying tumor cell responses to chemotherapy contributes significantly to the lack of effective treatment regimens. Here, paclitaxel, a first-line chemotherapeutic agent, was observed to interact synergistically with birinapant, a second mitochondrial-derived activator of caspases mimetic. Therefore, we investigated molecular-level drug interaction mechanisms using comprehensive, reproducible, and well-controlled ion-current-based MS1 quantification (IonStar). By analyzing 40 biological samples in a single batch, we compared temporal proteomic responses of PDAC cells treated with birinapant and paclitaxel, alone and combined. Using stringent criteria (e.g. strict false-discovery-rate (FDR) control, two peptides/protein), we quantified 4069 unique proteins confidently (99.8% without any missing data), and 541 proteins were significantly altered in the three treatment groups, with an FDR of <1%. Interestingly, most of these proteins were altered only by combined birinapant/paclitaxel, and these predominantly represented three biological processes: mitochondrial function, cell growth and apoptosis, and cell cycle arrest. Proteins responsible for activation of oxidative phosphorylation, fatty acid β-oxidation, and inactivation of aerobic glycolysis were altered largely by combined birinapant/paclitaxel compared with single drugs, suggesting the Warburg effect, which is critical for survival and proliferation of cancer cells, was alleviated by the combination treatment. Metabolic profiling was performed to confirm substantially greater suppression of the Warburg effect by the combined agents compared with either drug alone. Immunoassays confirmed proteomic data revealing changes in apoptosis/survival signaling pathways, such as inhibition of PI3K/AKT, JAK/STAT, and MAPK/ERK signal transduction, as well as induction of G2/M arrest, and showed the drug combination induced much more apoptosis than did single agents. Overall, this in-depth, large-scale proteomics study provided novel insights into molecular mechanisms underlying synergy of combined birinapant/paclitaxel and describes a proteomics/informatics pipeline that can be applied broadly to the development of cancer drug combination regimens.

Dataset Information

Proteomic Analysis of Combined Gemcitabine and Birinapant in Pancreatic Cancer Cells.

Publications

Proteomic Analysis of Combined Gemcitabine and Birinapant in Pancreatic Cancer Cells.

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