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Metabolomic profiling reveals a role for androgen in activating amino acid metabolism and methylation in prostate cancer cells.

Putluri N, Shojaie A, Vasu VT, Nalluri S, Vareed SK, Putluri V, Vivekanandan-Giri A, Byun J, Pennathur S, Sana TR, Fischer SM, Palapattu GS, Creighton CJ, Michailidis G, Sreekumar A - PLoS ONE (2011)

Bottom Line: Metastatic tumors are initially responsive to anti-androgen therapy, however become resistant to this regimen upon progression.Our findings indicate that androgen exposure results in elevation of amino acid metabolism and alteration of methylation potential in prostate cancer cells.Further, metabolic phenotyping studies confirm higher flux through pathways associated with amino acid metabolism in prostate cancer cells treated with androgen.

View Article: PubMed Central - PubMed

Affiliation: Cancer Center, Medical College of Georgia, Augusta, Georgia, United States of America.

ABSTRACT
Prostate cancer is the second leading cause of cancer related death in American men. Development and progression of clinically localized prostate cancer is highly dependent on androgen signaling. Metastatic tumors are initially responsive to anti-androgen therapy, however become resistant to this regimen upon progression. Genomic and proteomic studies have implicated a role for androgen in regulating metabolic processes in prostate cancer. However, there have been no metabolomic profiling studies conducted thus far that have examined androgen-regulated biochemical processes in prostate cancer. Here, we have used unbiased metabolomic profiling coupled with enrichment-based bioprocess mapping to obtain insights into the biochemical alterations mediated by androgen in prostate cancer cell lines. Our findings indicate that androgen exposure results in elevation of amino acid metabolism and alteration of methylation potential in prostate cancer cells. Further, metabolic phenotyping studies confirm higher flux through pathways associated with amino acid metabolism in prostate cancer cells treated with androgen. These findings provide insight into the potential biochemical processes regulated by androgen signaling in prostate cancer. Clinically, if validated, these pathways could be exploited to develop therapeutic strategies that supplement current androgen ablative treatments while the observed androgen-regulated metabolic signatures could be employed as biomarkers that presage the development of castrate-resistant prostate cancer.

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Metabolic alterations upon androgen-treatment of prostate cancer cells.A) Dendrogram representing unsupervised hierarchical clustering of the androgen-treated and control cells using their total metabolic profiles. B) Heat map showing 48 named differential metabolites that are altered in VCaP prostate cancer cells 24 h after treatment with 10 nM synthetic androgen (R1881) compared to untreated controls, (p<0.05, FDR = 20%), derived using a t-test coupled with permutations (n = 1,000) to determine the p-values for comparing the groups. The heat map was generated after log scaling and quantile normalization of the data. The color scheme is the same as in Fig. 2A. C) same as in (B) but for metabolic alterations after 48 h of androgen-treatment D) Correlation plot for metabolites altered at 24 h and 48 h post-androgen treatment in VCaP prostate cancer cells E) Network view of the molecular concept analysis for the metabolomic profiles of our “Androgen-induced metabolomic signature” (grey node). Each node represents a molecular concept or a set of biologically related genes. The node size is proportional to the number of genes in the concept. Each edge represents a statistically significant enrichment (FDR q-value<0.2). Enriched concepts describing “amino acid metabolism” and “methylation potential” are indicated by yellow and red bridges respectively.
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pone-0021417-g004: Metabolic alterations upon androgen-treatment of prostate cancer cells.A) Dendrogram representing unsupervised hierarchical clustering of the androgen-treated and control cells using their total metabolic profiles. B) Heat map showing 48 named differential metabolites that are altered in VCaP prostate cancer cells 24 h after treatment with 10 nM synthetic androgen (R1881) compared to untreated controls, (p<0.05, FDR = 20%), derived using a t-test coupled with permutations (n = 1,000) to determine the p-values for comparing the groups. The heat map was generated after log scaling and quantile normalization of the data. The color scheme is the same as in Fig. 2A. C) same as in (B) but for metabolic alterations after 48 h of androgen-treatment D) Correlation plot for metabolites altered at 24 h and 48 h post-androgen treatment in VCaP prostate cancer cells E) Network view of the molecular concept analysis for the metabolomic profiles of our “Androgen-induced metabolomic signature” (grey node). Each node represents a molecular concept or a set of biologically related genes. The node size is proportional to the number of genes in the concept. Each edge represents a statistically significant enrichment (FDR q-value<0.2). Enriched concepts describing “amino acid metabolism” and “methylation potential” are indicated by yellow and red bridges respectively.

Mentions: The metabolic compendia detected in 24 and 48 h androgen-treated cells contained a total of 1024 and 1146 compounds respectively, which completely distinguished androgen-treated cells from controls in an unsupervised manner (Figure 4A). Included in this time course compendia were 69 and 56 named metabolites that were identified at the two time points respectively (Figure 4B, C). Interestingly about 70% of the compounds altered by androgen showed a consistent pattern of change at 24 and 48 h time points (Figure 4D). Furthermore, similar to the results with PCa cell lines, the list of significant metabolites elevated by androgen-treatment predominantly contained amino acids and components of nitrogen metabolism pathway (Figure 4 B,C). Also, similar to our earlier findings with ARD cell lines, androgen treatment of VCaP lowered the SAM levels in these cells with a corresponding increase in levels of methylated metabolites like N-methyl glycine (sarcosine), 2-methylglutaric acid, dimethylglycine, methyl valine etc (Figure 4B). This suggests a possible role for androgen in altering methylation potential of prostate cancer cells which, as we reported earlier using tissues [27], is a critical component for tumor progression.


Metabolomic profiling reveals a role for androgen in activating amino acid metabolism and methylation in prostate cancer cells.

Putluri N, Shojaie A, Vasu VT, Nalluri S, Vareed SK, Putluri V, Vivekanandan-Giri A, Byun J, Pennathur S, Sana TR, Fischer SM, Palapattu GS, Creighton CJ, Michailidis G, Sreekumar A - PLoS ONE (2011)

Metabolic alterations upon androgen-treatment of prostate cancer cells.A) Dendrogram representing unsupervised hierarchical clustering of the androgen-treated and control cells using their total metabolic profiles. B) Heat map showing 48 named differential metabolites that are altered in VCaP prostate cancer cells 24 h after treatment with 10 nM synthetic androgen (R1881) compared to untreated controls, (p<0.05, FDR = 20%), derived using a t-test coupled with permutations (n = 1,000) to determine the p-values for comparing the groups. The heat map was generated after log scaling and quantile normalization of the data. The color scheme is the same as in Fig. 2A. C) same as in (B) but for metabolic alterations after 48 h of androgen-treatment D) Correlation plot for metabolites altered at 24 h and 48 h post-androgen treatment in VCaP prostate cancer cells E) Network view of the molecular concept analysis for the metabolomic profiles of our “Androgen-induced metabolomic signature” (grey node). Each node represents a molecular concept or a set of biologically related genes. The node size is proportional to the number of genes in the concept. Each edge represents a statistically significant enrichment (FDR q-value<0.2). Enriched concepts describing “amino acid metabolism” and “methylation potential” are indicated by yellow and red bridges respectively.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3138744&req=5

pone-0021417-g004: Metabolic alterations upon androgen-treatment of prostate cancer cells.A) Dendrogram representing unsupervised hierarchical clustering of the androgen-treated and control cells using their total metabolic profiles. B) Heat map showing 48 named differential metabolites that are altered in VCaP prostate cancer cells 24 h after treatment with 10 nM synthetic androgen (R1881) compared to untreated controls, (p<0.05, FDR = 20%), derived using a t-test coupled with permutations (n = 1,000) to determine the p-values for comparing the groups. The heat map was generated after log scaling and quantile normalization of the data. The color scheme is the same as in Fig. 2A. C) same as in (B) but for metabolic alterations after 48 h of androgen-treatment D) Correlation plot for metabolites altered at 24 h and 48 h post-androgen treatment in VCaP prostate cancer cells E) Network view of the molecular concept analysis for the metabolomic profiles of our “Androgen-induced metabolomic signature” (grey node). Each node represents a molecular concept or a set of biologically related genes. The node size is proportional to the number of genes in the concept. Each edge represents a statistically significant enrichment (FDR q-value<0.2). Enriched concepts describing “amino acid metabolism” and “methylation potential” are indicated by yellow and red bridges respectively.
Mentions: The metabolic compendia detected in 24 and 48 h androgen-treated cells contained a total of 1024 and 1146 compounds respectively, which completely distinguished androgen-treated cells from controls in an unsupervised manner (Figure 4A). Included in this time course compendia were 69 and 56 named metabolites that were identified at the two time points respectively (Figure 4B, C). Interestingly about 70% of the compounds altered by androgen showed a consistent pattern of change at 24 and 48 h time points (Figure 4D). Furthermore, similar to the results with PCa cell lines, the list of significant metabolites elevated by androgen-treatment predominantly contained amino acids and components of nitrogen metabolism pathway (Figure 4 B,C). Also, similar to our earlier findings with ARD cell lines, androgen treatment of VCaP lowered the SAM levels in these cells with a corresponding increase in levels of methylated metabolites like N-methyl glycine (sarcosine), 2-methylglutaric acid, dimethylglycine, methyl valine etc (Figure 4B). This suggests a possible role for androgen in altering methylation potential of prostate cancer cells which, as we reported earlier using tissues [27], is a critical component for tumor progression.

Bottom Line: Metastatic tumors are initially responsive to anti-androgen therapy, however become resistant to this regimen upon progression.Our findings indicate that androgen exposure results in elevation of amino acid metabolism and alteration of methylation potential in prostate cancer cells.Further, metabolic phenotyping studies confirm higher flux through pathways associated with amino acid metabolism in prostate cancer cells treated with androgen.

View Article: PubMed Central - PubMed

Affiliation: Cancer Center, Medical College of Georgia, Augusta, Georgia, United States of America.

ABSTRACT
Prostate cancer is the second leading cause of cancer related death in American men. Development and progression of clinically localized prostate cancer is highly dependent on androgen signaling. Metastatic tumors are initially responsive to anti-androgen therapy, however become resistant to this regimen upon progression. Genomic and proteomic studies have implicated a role for androgen in regulating metabolic processes in prostate cancer. However, there have been no metabolomic profiling studies conducted thus far that have examined androgen-regulated biochemical processes in prostate cancer. Here, we have used unbiased metabolomic profiling coupled with enrichment-based bioprocess mapping to obtain insights into the biochemical alterations mediated by androgen in prostate cancer cell lines. Our findings indicate that androgen exposure results in elevation of amino acid metabolism and alteration of methylation potential in prostate cancer cells. Further, metabolic phenotyping studies confirm higher flux through pathways associated with amino acid metabolism in prostate cancer cells treated with androgen. These findings provide insight into the potential biochemical processes regulated by androgen signaling in prostate cancer. Clinically, if validated, these pathways could be exploited to develop therapeutic strategies that supplement current androgen ablative treatments while the observed androgen-regulated metabolic signatures could be employed as biomarkers that presage the development of castrate-resistant prostate cancer.

Show MeSH
Related in: MedlinePlus