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A Boolean network of the crosstalk between IGF and Wnt signaling in aging satellite cells.

ABSTRACT: Aging is a complex biological process, which determines the life span of an organism. Insulin-like growth factor (IGF) and Wnt signaling pathways govern the process of aging. Both pathways share common downstream targets that allow competitive crosstalk between these branches. Of note, a shift from IGF to Wnt signaling has been observed during aging of satellite cells. Biological regulatory networks necessary to recreate aging have not yet been discovered. Here, we established a mathematical in silico model that robustly recapitulates the crosstalk between IGF and Wnt signaling. Strikingly, it predicts critical nodes following a shift from IGF to Wnt signaling. These findings indicate that this shift might cause age-related diseases.

SUBMITTER: Siegle L

PROVIDER: S-EPMC5875862 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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A Boolean network of the crosstalk between IGF and Wnt signaling in aging satellite cells.

Siegle Lea L Schwab Julian D JD Kühlwein Silke D SD Lausser Ludwig L Tümpel Stefan S Pfister Astrid S AS Kühl Michael M Kestler Hans A HA

PloS one 20180329 3

Aging is a complex biological process, which determines the life span of an organism. Insulin-like growth factor (IGF) and Wnt signaling pathways govern the process of aging. Both pathways share common downstream targets that allow competitive crosstalk between these branches. Of note, a shift from IGF to Wnt signaling has been observed during aging of satellite cells. Biological regulatory networks necessary to recreate aging have not yet been discovered. Here, we established a mathematical in ...[more]

PMID: 29596489

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Project description:BackgroundCellular response to external stimuli requires propagation of corresponding signals through molecular signaling pathways. However, signaling pathways are not isolated information highways, but rather interact in a number of ways forming sophisticated signaling networks. Since defects in signaling pathways are associated with many serious diseases, understanding of the crosstalk between them is fundamental for designing molecularly targeted therapy. Unfortunately, we still lack technology that would allow high throughput detailed measurement of activity of individual signaling molecules and their interactions. This necessitates developing methods to prioritize selection of the molecules such that measuring their activity would be most informative for understanding the crosstalk. Furthermore, absence of the reaction coefficients necessary for detailed modeling of signal propagation raises the question whether simple parameter-free models could provide useful information about such pathways.ResultsWe study the combined signaling network of three major pro-survival signaling pathways: Epidermal Growth Factor Receptor (EGFR), Insulin-like Growth Factor-1 Receptor (IGF-1R), and Insulin Receptor (IR). Our study involves static analysis and dynamic modeling of this network, as well as an experimental verification of the model by measuring the response of selected signaling molecules to differential stimulation of EGF, IGF and insulin receptors. We introduced two novel measures of the importance of a node in the context of such crosstalk. Based on these measures several molecules, namely Erk1/2, Akt1, Jnk, p70S6K, were selected for monitoring in the network simulation and for experimental studies. Our simulation method relies on the Boolean network model combined with stochastic propagation of the signal. Most (although not all) trends suggested by the simulations have been confirmed by experiments.ConclusionThe simple model implemented in this paper provides a valuable first step in modeling signaling networks. However, to obtain a fully predictive model, a more detailed knowledge regarding parameters of individual interactions might be necessary.

Project description:Introduction:Prostate cancer (PCa) is the most commonly diagnosed cancer and the third leading cause of cancer-related death in males in the United States. Despite the initial efficacy of androgen deprivation therapy in prostate cancer (PCa) patients, most patients progress to castration-resistant prostate cancer. However, the mechanisms underlying the androgen-independent progression of PCa remain largely unknown. Methods:In this study, we established a PCa cell line (LNCaP-AI) by maintaining LNCaP cells under androgen-depleted conditions. To explore the cellular and molecular mechanisms of androgen-independent growth of PCa, we analyzed the gene expression patterns in androgen-independent prostate cancer (AIPC) compared with that in androgen-dependent prostate cancer (ADPC). KEGG pathway analysis revealed that Wnt signaling pathways were activated after androgen deprivation therapy (ADT). In vitro experiments showed that the inhibition of Wnt pathway reduced AIPC cell growth by inhibiting cell cycle progression and promoting apoptosis. Furthermore, WNT5A, LEF1 were identified as direct targets of AR by chromatin immunoprecipitation (ChIP) assay and public ChIP-seq datasets analysis. Results:In the present study, we found a regulatory mechanism through which crosstalk between androgen receptor (AR) and Wnt signals promoted androgen-independent conversion of PCa. The Wnt pathway was inhibited by androgen in androgen-dependent prostate cancer cells, but this blocking effect was not elicited in androgen-independent prostate cancer (AIPC) cells. Moreover, Wnt pathway genes WNT5A and LEF1 were directly downregulated by AR. In vitro experiments showed that inhibition of the Wnt pathways repressed AIPC cell growth by inhibiting cell cycle progression and promoting apoptosis. We found that WNT5A and LEF1 were downregulated in low-grade PCa but upregulated in metastatic PCa. Conclusion:In summary, we revealed that crosstalk between AR and Wnt signaling pathways promotes androgen-independent growth of PCa, which may provide novel therapeutic opportunities for castration-resistant prostate cancer.

Dataset Information

A Boolean network of the crosstalk between IGF and Wnt signaling in aging satellite cells.

Publications

A Boolean network of the crosstalk between IGF and Wnt signaling in aging satellite cells.

Similar Datasets

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