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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.

Original publication

DOI

10.18632/oncotarget.3494

Type

Journal article

Journal

Oncotarget

Publication Date

20/05/2015

Volume

6

Pages

12587 - 12602

Keywords

cancer, metabolism, nucleotide, prostate, transcription, Blotting, Western, Cell Nucleolus, Chromatin Immunoprecipitation, Gene Expression Regulation, Neoplastic, Humans, IMP Dehydrogenase, Immunohistochemistry, Male, Prostatic Neoplasms, Proto-Oncogene Proteins c-myc, Purines, Real-Time Polymerase Chain Reaction, Receptors, Androgen, Tissue Array Analysis