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Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer.

Barfeld SJ, Fazli L, Persson M, Marjavaara L, Urbanucci A, Kaukoniemi KM, Rennie PS, Ceder Y, Chabes A, Visakorpi T, Mills IG - Oncotarget (2015)

Bottom Line: In this study, we report that in PCa cells de novo purine biosynthesis and the subsequent conversion to XMP is tightly regulated by MYC and independent of AR activity.We characterized two enzymes, PAICS and IMPDH2, within the pathway as PCa biomarkers in tissue samples and report increased efficacy of established anti-androgens in combination with a clinically approved IMPDH inhibitor, mycophenolic acid (MPA).In conclusion, targeting purine biosynthesis provides an opportunity to perturb PCa metabolism and enhance tumour suppressive stress responses.

View Article: PubMed Central - PubMed

Affiliation: Prostate Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway.

ABSTRACT
The androgen receptor is a key transcription factor contributing to the development of all stages of prostate cancer (PCa). In addition, other transcription factors have been associated with poor prognosis in PCa, amongst which c-Myc (MYC) is a well-established oncogene in many other cancers. We have previously reported that the AR promotes glycolysis and anabolic metabolism; many of these metabolic pathways are also MYC-regulated in other cancers. In this study, we report that in PCa cells de novo purine biosynthesis and the subsequent conversion to XMP is tightly regulated by MYC and independent of AR activity. We characterized two enzymes, PAICS and IMPDH2, within the pathway as PCa biomarkers in tissue samples and report increased efficacy of established anti-androgens in combination with a clinically approved IMPDH inhibitor, mycophenolic acid (MPA). Treatment with MPA led to a significant reduction in cellular guanosine triphosphate (GTP) levels accompanied by nucleolar stress and p53 stabilization. In conclusion, targeting purine biosynthesis provides an opportunity to perturb PCa metabolism and enhance tumour suppressive stress responses.

No MeSH data available.


Related in: MedlinePlus

PAICS and IMPDH2 are overexpressed in prostate cancer patientsA. Schematic overview of the de novo purine biosynthesis pathway with direct MYC targets highlighted in yellow. B. Real-time PCR results on clinical samples. Total RNA was collected from prostate biopsies of patients suffering from benign hyperplasia (BPH), prostate cancer (PCa) or castrate-resistant prostate cancer (CRPC). The expression levels of MYC, PAICS and IMPDH2 were measured using real-time PCR and normalized to the expression of TATA-box binding protein (TBP). The line displays the mean value and significance was determined using one-way analysis of variation (ANOVA) with Bonferroni's multiple comparison test. n = 15–27 C. Immunohistochemistry data. Staining intensities of PAICS and IMPDH2 in patient biopsies with BPH, PCa CRPC, hormone-naïve, short and long NHT were assessed. Intensities divided into four groups (negative = 0, weak = 1, moderate = 2 and strong = 3) and used for subsequent analysis. Statistical analysis was performed using one-way analysis of variation (ANOVA) with Bonferroni's multiple comparison test. n = 20–113 cores D. Representative images of the TMAs for PAICS (left) and IMPDH2 (right).
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Figure 2: PAICS and IMPDH2 are overexpressed in prostate cancer patientsA. Schematic overview of the de novo purine biosynthesis pathway with direct MYC targets highlighted in yellow. B. Real-time PCR results on clinical samples. Total RNA was collected from prostate biopsies of patients suffering from benign hyperplasia (BPH), prostate cancer (PCa) or castrate-resistant prostate cancer (CRPC). The expression levels of MYC, PAICS and IMPDH2 were measured using real-time PCR and normalized to the expression of TATA-box binding protein (TBP). The line displays the mean value and significance was determined using one-way analysis of variation (ANOVA) with Bonferroni's multiple comparison test. n = 15–27 C. Immunohistochemistry data. Staining intensities of PAICS and IMPDH2 in patient biopsies with BPH, PCa CRPC, hormone-naïve, short and long NHT were assessed. Intensities divided into four groups (negative = 0, weak = 1, moderate = 2 and strong = 3) and used for subsequent analysis. Statistical analysis was performed using one-way analysis of variation (ANOVA) with Bonferroni's multiple comparison test. n = 20–113 cores D. Representative images of the TMAs for PAICS (left) and IMPDH2 (right).

Mentions: Taking together both the expression and ChIP approaches, we defined direct MYC regulated genes as genes that both mirrored changes in MYC levels in both directions and exhibited MYC binding in their respective promoter. Thus, PPAT, GART, PFAS, PAICS, ADSL and IMPDH2 are under the direct control of MYC in two metastatic PCa cell lines, as illustrated in Figure 2A.


Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer.

Barfeld SJ, Fazli L, Persson M, Marjavaara L, Urbanucci A, Kaukoniemi KM, Rennie PS, Ceder Y, Chabes A, Visakorpi T, Mills IG - Oncotarget (2015)

PAICS and IMPDH2 are overexpressed in prostate cancer patientsA. Schematic overview of the de novo purine biosynthesis pathway with direct MYC targets highlighted in yellow. B. Real-time PCR results on clinical samples. Total RNA was collected from prostate biopsies of patients suffering from benign hyperplasia (BPH), prostate cancer (PCa) or castrate-resistant prostate cancer (CRPC). The expression levels of MYC, PAICS and IMPDH2 were measured using real-time PCR and normalized to the expression of TATA-box binding protein (TBP). The line displays the mean value and significance was determined using one-way analysis of variation (ANOVA) with Bonferroni's multiple comparison test. n = 15–27 C. Immunohistochemistry data. Staining intensities of PAICS and IMPDH2 in patient biopsies with BPH, PCa CRPC, hormone-naïve, short and long NHT were assessed. Intensities divided into four groups (negative = 0, weak = 1, moderate = 2 and strong = 3) and used for subsequent analysis. Statistical analysis was performed using one-way analysis of variation (ANOVA) with Bonferroni's multiple comparison test. n = 20–113 cores D. Representative images of the TMAs for PAICS (left) and IMPDH2 (right).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494960&req=5

Figure 2: PAICS and IMPDH2 are overexpressed in prostate cancer patientsA. Schematic overview of the de novo purine biosynthesis pathway with direct MYC targets highlighted in yellow. B. Real-time PCR results on clinical samples. Total RNA was collected from prostate biopsies of patients suffering from benign hyperplasia (BPH), prostate cancer (PCa) or castrate-resistant prostate cancer (CRPC). The expression levels of MYC, PAICS and IMPDH2 were measured using real-time PCR and normalized to the expression of TATA-box binding protein (TBP). The line displays the mean value and significance was determined using one-way analysis of variation (ANOVA) with Bonferroni's multiple comparison test. n = 15–27 C. Immunohistochemistry data. Staining intensities of PAICS and IMPDH2 in patient biopsies with BPH, PCa CRPC, hormone-naïve, short and long NHT were assessed. Intensities divided into four groups (negative = 0, weak = 1, moderate = 2 and strong = 3) and used for subsequent analysis. Statistical analysis was performed using one-way analysis of variation (ANOVA) with Bonferroni's multiple comparison test. n = 20–113 cores D. Representative images of the TMAs for PAICS (left) and IMPDH2 (right).
Mentions: Taking together both the expression and ChIP approaches, we defined direct MYC regulated genes as genes that both mirrored changes in MYC levels in both directions and exhibited MYC binding in their respective promoter. Thus, PPAT, GART, PFAS, PAICS, ADSL and IMPDH2 are under the direct control of MYC in two metastatic PCa cell lines, as illustrated in Figure 2A.

Bottom Line: In this study, we report that in PCa cells de novo purine biosynthesis and the subsequent conversion to XMP is tightly regulated by MYC and independent of AR activity.We characterized two enzymes, PAICS and IMPDH2, within the pathway as PCa biomarkers in tissue samples and report increased efficacy of established anti-androgens in combination with a clinically approved IMPDH inhibitor, mycophenolic acid (MPA).In conclusion, targeting purine biosynthesis provides an opportunity to perturb PCa metabolism and enhance tumour suppressive stress responses.

View Article: PubMed Central - PubMed

Affiliation: Prostate Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway.

ABSTRACT
The androgen receptor is a key transcription factor contributing to the development of all stages of prostate cancer (PCa). In addition, other transcription factors have been associated with poor prognosis in PCa, amongst which c-Myc (MYC) is a well-established oncogene in many other cancers. We have previously reported that the AR promotes glycolysis and anabolic metabolism; many of these metabolic pathways are also MYC-regulated in other cancers. In this study, we report that in PCa cells de novo purine biosynthesis and the subsequent conversion to XMP is tightly regulated by MYC and independent of AR activity. We characterized two enzymes, PAICS and IMPDH2, within the pathway as PCa biomarkers in tissue samples and report increased efficacy of established anti-androgens in combination with a clinically approved IMPDH inhibitor, mycophenolic acid (MPA). Treatment with MPA led to a significant reduction in cellular guanosine triphosphate (GTP) levels accompanied by nucleolar stress and p53 stabilization. In conclusion, targeting purine biosynthesis provides an opportunity to perturb PCa metabolism and enhance tumour suppressive stress responses.

No MeSH data available.


Related in: MedlinePlus