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Inhibition of glycogen phosphorylation induces changes in cellular proteome and signaling pathways in MIA pancreatic cancer cells.

ABSTRACT: Novel quantitative proteomic approaches were used to study the effects of inhibition of glycogen phosphorylase on proteome and signaling pathways in MIA PaCa-2 pancreatic cancer cells.We performed quantitative proteomic analysis in MIA PaCa-2 cancer cells treated with a stratified dose of CP-320626 (5-chloro-1H-indole-2-carboxylic acid [1-(4-fuorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2 oxoethyl] amide) (25, 50, and 100 ?M). The effect of metabolic inhibition on cellular protein turnover dynamics was also studied using the modified SILAC (stable isotope labeling with amino acids in cell culture) method.A total of 22 protein spots and 4 phosphoprotein spots were quantitatively analyzed. We found that dynamic expression of total proteins and phosphoproteins was significantly changed in MIA PaCa-2 cells treated with an incremental dose of CP-320626. Functional analyses suggested that most of the proteins differentially expressed were in the pathways of mitogen-activated protein kinase/extracellular signal-regulated kinase and tumor necrosis factor ?/nuclear factor ?B.Signaling pathways and metabolic pathways share many common cofactors and substrates forming an extended metabolic network. The restriction of substrate through 1 pathway such as inhibition of glycogen phosphorylation induces pervasive metabolomic and proteomic changes manifested in protein synthesis, breakdown, and posttranslational modification of signaling molecules. Our results suggest that quantitative proteomic is an important approach to understand the interaction between metabolism and signaling pathways.

SUBMITTER: Ma D

PROVIDER: S-EPMC3306546 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Inhibition of glycogen phosphorylation induces changes in cellular proteome and signaling pathways in MIA pancreatic cancer cells.

Ma Danjun D Wang Jiarui J Zhao Yingchun Y Lee Wai-Nang Paul WN Xiao Jing J Go Vay Liang W VL Wang Qi Q Recker Robert R RR Xiao Gary Guishan GG

Pancreas 20120401 3

<h4>Objectives</h4>Novel quantitative proteomic approaches were used to study the effects of inhibition of glycogen phosphorylase on proteome and signaling pathways in MIA PaCa-2 pancreatic cancer cells.<h4>Methods</h4>We performed quantitative proteomic analysis in MIA PaCa-2 cancer cells treated with a stratified dose of CP-320626 (5-chloro-1H-indole-2-carboxylic acid [1-(4-fuorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2 oxoethyl] amide) (25, 50, and 100 μM). The effect of metabolic inhibition on c ...[more]

PMID: 22158071

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Project description:BackgroundIn early pregnancy, differentiating between a normal intrauterine pregnancy (IUP) and abnormal gestations including early pregnancy loss (EPL) or ectopic pregnancy (EP) is a major clinical challenge when ultrasound is not yet diagnostic. Clinical treatments for these outcomes are drastically different making early, accurate diagnosis imperative. Hence, a greater understanding of the biological mechanisms involved in these early pregnancy complications could lead to new molecular diagnostics.MethodsTrophoblast and endometrial tissue was collected from consenting women having an IUP (n = 4), EPL (n = 4), or EP (n = 2). Samples were analyzed by LC-MS/MS followed by a label-free proteomics analysis in an exploratory study. For each tissue type, pairwise comparisons of different pregnancy outcomes (EPL vs. IUP and EP vs. IUP) were performed, and protein changes having a fold change ≥ 3 and a Student's t-test p-value ≤ 0.05 were defined as significant. Pathway and network classification tools were used to group significantly changing proteins based on their functional similarities.ResultsA total of 4792 and 4757 proteins were identified in decidua and trophoblast proteomes. For decidua, 125 protein levels (2.6% of the proteome) were significantly different between EP and IUP, whereas EPL and IUP decidua were more similar with only 68 (1.4%) differences. For trophoblasts, there were 66 (1.4%) differences between EPL and IUP. However, the largest group of 344 differences (7.2%) was observed between EP and IUP trophoblasts. In both tissues, proteins associated with ECM remodeling, cell adhesion and metabolic pathways showed decreases in EP specimens compared with IUP and EPL. In trophoblasts, EP showed elevation of inflammatory and immune response pathways.ConclusionsOverall, differences between an EP and IUP are greater than the changes observed when comparing ongoing IUP and nonviable intrauterine pregnancies (EPL) in both decidua and trophoblast proteomes. Furthermore, differences between EP and IUP were much higher in the trophoblast than in the decidua. This observation is true for the total number of protein changes as well as the extent of changes in upstream regulators and related pathways. This suggests that biomarkers and mechanisms of trophoblast function may be the best predictors of early pregnancy location and viability.

Dataset Information

Inhibition of glycogen phosphorylation induces changes in cellular proteome and signaling pathways in MIA pancreatic cancer cells.

Publications

Inhibition of glycogen phosphorylation induces changes in cellular proteome and signaling pathways in MIA pancreatic cancer cells.

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