Dataset Information

Multi-Scale Network Model Supported by Proteomics for Analysis of Combined Gemcitabine and Birinapant Effects in Pancreatic Cancer Cells.

ABSTRACT: Gemcitabine combined with birinapant, an inhibitor of apoptosis protein antagonist, acts synergistically to reduce pancreatic cancer cell proliferation. A large-scale proteomics dataset provided rich time-series data on proteome-level changes that reflect the underlying biological system and mechanisms of action of these drugs. A multiscale network model was developed to link the signaling pathways of cell cycle regulation, DNA damage response, DNA repair, apoptosis, nuclear factor-kappa ? (NF-??), and mitogen-activated protein kinase (MAPK)-p38 to cell cycle progression, proliferation, and death. After validating the network model under different conditions, the Sobol Sensitivity Analysis was applied to identify promising targets to enhance gemcitabine efficacy. The effects of p53 silencing and combining curcumin with gemcitabine were also tested with the developed model. Merging proteomics analysis with systems modeling facilitates the characterization of quantitative relations among relevant signaling pathways in drug action and resistance, and such multiscale network models could be applied for prediction of combination efficacy and target selection.

SUBMITTER: Zhu X

PROVIDER: S-EPMC6157671 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Multi-Scale Network Model Supported by Proteomics for Analysis of Combined Gemcitabine and Birinapant Effects in Pancreatic Cancer Cells.

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

CPT: pharmacometrics & systems pharmacology 20180809 9

Gemcitabine combined with birinapant, an inhibitor of apoptosis protein antagonist, acts synergistically to reduce pancreatic cancer cell proliferation. A large-scale proteomics dataset provided rich time-series data on proteome-level changes that reflect the underlying biological system and mechanisms of action of these drugs. A multiscale network model was developed to link the signaling pathways of cell cycle regulation, DNA damage response, DNA repair, apoptosis, nuclear factor-kappa β (NF-κ ...[more]

PMID: 30084546

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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 ?-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

Multi-Scale Network Model Supported by Proteomics for Analysis of Combined Gemcitabine and Birinapant Effects in Pancreatic Cancer Cells.

Publications

Multi-Scale Network Model Supported by Proteomics for Analysis of Combined Gemcitabine and Birinapant Effects in Pancreatic Cancer Cells.

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