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Analysis of the molecular networks in androgen dependent and independent prostate cancer revealed fragile and robust subsystems.

Tasseff R, Nayak S, Salim S, Kaushik P, Rizvi N, Varner JD - PLoS ONE (2010)

Bottom Line: Further analysis suggested a positive synergy between the MAPK and Akt signaling axes and the translation of key proliferative markers like cyclin D in androgen-independent cells.Taken together, the results support the targeting of both the Akt and MAPK pathways.Moreover, the analysis suggested that direct targeting of the translational machinery, specifically eIF4E, could be efficacious in androgen-independent prostate cancers.

View Article: PubMed Central - PubMed

Affiliation: School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, United States of America.

ABSTRACT
Androgen ablation therapy is currently the primary treatment for metastatic prostate cancer. Unfortunately, in nearly all cases, androgen ablation fails to permanently arrest cancer progression. As androgens like testosterone are withdrawn, prostate cancer cells lose their androgen sensitivity and begin to proliferate without hormone growth factors. In this study, we constructed and analyzed a mathematical model of the integration between hormone growth factor signaling, androgen receptor activation, and the expression of cyclin D and Prostate-Specific Antigen in human LNCaP prostate adenocarcinoma cells. The objective of the study was to investigate which signaling systems were important in the loss of androgen dependence. The model was formulated as a set of ordinary differential equations which described 212 species and 384 interactions, including both the mRNA and protein levels for key species. An ensemble approach was chosen to constrain model parameters and to estimate the impact of parametric uncertainty on model predictions. Model parameters were identified using 14 steady-state and dynamic LNCaP data sets taken from literature sources. Alterations in the rate of Prostatic Acid Phosphatase expression was sufficient to capture varying levels of androgen dependence. Analysis of the model provided insight into the importance of network components as a function of androgen dependence. The importance of androgen receptor availability and the MAPK/Akt signaling axes was independent of androgen status. Interestingly, androgen receptor availability was important even in androgen-independent LNCaP cells. Translation became progressively more important in androgen-independent LNCaP cells. Further analysis suggested a positive synergy between the MAPK and Akt signaling axes and the translation of key proliferative markers like cyclin D in androgen-independent cells. Taken together, the results support the targeting of both the Akt and MAPK pathways. Moreover, the analysis suggested that direct targeting of the translational machinery, specifically eIF4E, could be efficacious in androgen-independent prostate cancers.

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Independent model predictions versus experimental observations.A Ensemble prediction of cyclin D expression following the addition of DHT at 1 hour to C-33 clones. The ensemble predicted a dose dependent increase of cyclin D at 24 hours after DHT addition. Experimental data was adapted from Barnes-Ellerbe et al. [60]. B Predicted effect of an AR knockdown on PSA expression following the addition of androgen at 1 hour to C-33 wild-type and C-33 AR knock-down clones. The ensemble predicted an approximate 50% decrease in androgen stimulated PSA expression due to AR knock-down 72 hours after treatment. Experimental data was reported by Eder et al. [61]. The error bar denotes one standard deviation centered about the ensemble mean.
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pone-0008864-g006: Independent model predictions versus experimental observations.A Ensemble prediction of cyclin D expression following the addition of DHT at 1 hour to C-33 clones. The ensemble predicted a dose dependent increase of cyclin D at 24 hours after DHT addition. Experimental data was adapted from Barnes-Ellerbe et al. [60]. B Predicted effect of an AR knockdown on PSA expression following the addition of androgen at 1 hour to C-33 wild-type and C-33 AR knock-down clones. The ensemble predicted an approximate 50% decrease in androgen stimulated PSA expression due to AR knock-down 72 hours after treatment. Experimental data was reported by Eder et al. [61]. The error bar denotes one standard deviation centered about the ensemble mean.

Mentions: The model recapitulated the positive feedback between Her2 induced MAPK activation and androgen action. Several studies have demonstrated that MAPK can activate AR in the absence of hormone stimulation. Activated AR transcriptionally down-regulates cPAcP expression which in turn increases Her2 activation. Both Her2 dimerization along with the traditional EGFR-growth factor pathway can activate MAPK, leading to a positive feedback loop. However, typical growth factor induced MAPK activation is transient whereas de-regulated Her2 induced MAPK activation is persistent. The MAPK module in the model described both activation pathways. Growth factor dependent MAPK activation was constrained by dynamic measurements of phosphorylated ERK (ERKpp) levels following stimulation of EGFR with 8nM EGF (Fig. 5D). The EGF induced ERKpp data was taken from HeLa cells [30]. However, we expect transient EGF-induced MAPK activation in LNCaP cells will be qualitatively similar to HeLa given the conserved nature of mitogenic signaling. We constrained Her2 induced MAPK activation using cyclin D protein expression data in C-33 and C-81 cells without androgen following PAcP expression (Fig. 5C). Cyclin D expression was coupled to ERK through the ETS and AP1 transcription factors, both of which activate cyclin D expression [59]. Her2 induced MAPK activation led to a persistent ETSp signal compared to ETS activation following EGFR-induced MAPK activation (Fig. 5D, inset). Nominally, C-33 cells have lower cyclin D expression compared to C-81 (Fig. 5C, lane 1 and 4). The difference in cyclin D expression between C-33 and C-81 cells was qualitatively consistent with increased C-81 proliferation [13]. While the expression of cPAcP in C-81 reduced cyclin D levels (Fig. 5C, lane 2), sPAcP expression resulted in no change (Fig. 5C, lane 3). Furthermore, the model predicted a dose dependent increase in C-33 cyclin D levels 24 hours after addition of DHT (Fig. 6A). Although the cyclin D increase is only notable in response to high levels of DHT (10 or 100nM) the prediction is qualitatively consistent with experimental data not included in the ensemble calculations [60].


Analysis of the molecular networks in androgen dependent and independent prostate cancer revealed fragile and robust subsystems.

Tasseff R, Nayak S, Salim S, Kaushik P, Rizvi N, Varner JD - PLoS ONE (2010)

Independent model predictions versus experimental observations.A Ensemble prediction of cyclin D expression following the addition of DHT at 1 hour to C-33 clones. The ensemble predicted a dose dependent increase of cyclin D at 24 hours after DHT addition. Experimental data was adapted from Barnes-Ellerbe et al. [60]. B Predicted effect of an AR knockdown on PSA expression following the addition of androgen at 1 hour to C-33 wild-type and C-33 AR knock-down clones. The ensemble predicted an approximate 50% decrease in androgen stimulated PSA expression due to AR knock-down 72 hours after treatment. Experimental data was reported by Eder et al. [61]. The error bar denotes one standard deviation centered about the ensemble mean.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2812491&req=5

pone-0008864-g006: Independent model predictions versus experimental observations.A Ensemble prediction of cyclin D expression following the addition of DHT at 1 hour to C-33 clones. The ensemble predicted a dose dependent increase of cyclin D at 24 hours after DHT addition. Experimental data was adapted from Barnes-Ellerbe et al. [60]. B Predicted effect of an AR knockdown on PSA expression following the addition of androgen at 1 hour to C-33 wild-type and C-33 AR knock-down clones. The ensemble predicted an approximate 50% decrease in androgen stimulated PSA expression due to AR knock-down 72 hours after treatment. Experimental data was reported by Eder et al. [61]. The error bar denotes one standard deviation centered about the ensemble mean.
Mentions: The model recapitulated the positive feedback between Her2 induced MAPK activation and androgen action. Several studies have demonstrated that MAPK can activate AR in the absence of hormone stimulation. Activated AR transcriptionally down-regulates cPAcP expression which in turn increases Her2 activation. Both Her2 dimerization along with the traditional EGFR-growth factor pathway can activate MAPK, leading to a positive feedback loop. However, typical growth factor induced MAPK activation is transient whereas de-regulated Her2 induced MAPK activation is persistent. The MAPK module in the model described both activation pathways. Growth factor dependent MAPK activation was constrained by dynamic measurements of phosphorylated ERK (ERKpp) levels following stimulation of EGFR with 8nM EGF (Fig. 5D). The EGF induced ERKpp data was taken from HeLa cells [30]. However, we expect transient EGF-induced MAPK activation in LNCaP cells will be qualitatively similar to HeLa given the conserved nature of mitogenic signaling. We constrained Her2 induced MAPK activation using cyclin D protein expression data in C-33 and C-81 cells without androgen following PAcP expression (Fig. 5C). Cyclin D expression was coupled to ERK through the ETS and AP1 transcription factors, both of which activate cyclin D expression [59]. Her2 induced MAPK activation led to a persistent ETSp signal compared to ETS activation following EGFR-induced MAPK activation (Fig. 5D, inset). Nominally, C-33 cells have lower cyclin D expression compared to C-81 (Fig. 5C, lane 1 and 4). The difference in cyclin D expression between C-33 and C-81 cells was qualitatively consistent with increased C-81 proliferation [13]. While the expression of cPAcP in C-81 reduced cyclin D levels (Fig. 5C, lane 2), sPAcP expression resulted in no change (Fig. 5C, lane 3). Furthermore, the model predicted a dose dependent increase in C-33 cyclin D levels 24 hours after addition of DHT (Fig. 6A). Although the cyclin D increase is only notable in response to high levels of DHT (10 or 100nM) the prediction is qualitatively consistent with experimental data not included in the ensemble calculations [60].

Bottom Line: Further analysis suggested a positive synergy between the MAPK and Akt signaling axes and the translation of key proliferative markers like cyclin D in androgen-independent cells.Taken together, the results support the targeting of both the Akt and MAPK pathways.Moreover, the analysis suggested that direct targeting of the translational machinery, specifically eIF4E, could be efficacious in androgen-independent prostate cancers.

View Article: PubMed Central - PubMed

Affiliation: School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, United States of America.

ABSTRACT
Androgen ablation therapy is currently the primary treatment for metastatic prostate cancer. Unfortunately, in nearly all cases, androgen ablation fails to permanently arrest cancer progression. As androgens like testosterone are withdrawn, prostate cancer cells lose their androgen sensitivity and begin to proliferate without hormone growth factors. In this study, we constructed and analyzed a mathematical model of the integration between hormone growth factor signaling, androgen receptor activation, and the expression of cyclin D and Prostate-Specific Antigen in human LNCaP prostate adenocarcinoma cells. The objective of the study was to investigate which signaling systems were important in the loss of androgen dependence. The model was formulated as a set of ordinary differential equations which described 212 species and 384 interactions, including both the mRNA and protein levels for key species. An ensemble approach was chosen to constrain model parameters and to estimate the impact of parametric uncertainty on model predictions. Model parameters were identified using 14 steady-state and dynamic LNCaP data sets taken from literature sources. Alterations in the rate of Prostatic Acid Phosphatase expression was sufficient to capture varying levels of androgen dependence. Analysis of the model provided insight into the importance of network components as a function of androgen dependence. The importance of androgen receptor availability and the MAPK/Akt signaling axes was independent of androgen status. Interestingly, androgen receptor availability was important even in androgen-independent LNCaP cells. Translation became progressively more important in androgen-independent LNCaP cells. Further analysis suggested a positive synergy between the MAPK and Akt signaling axes and the translation of key proliferative markers like cyclin D in androgen-independent cells. Taken together, the results support the targeting of both the Akt and MAPK pathways. Moreover, the analysis suggested that direct targeting of the translational machinery, specifically eIF4E, could be efficacious in androgen-independent prostate cancers.

Show MeSH
Related in: MedlinePlus