title: Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer.
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.
authors: Prostate Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway.
authors: Stefan J
authors: SJ
authors: Barfeld
authors: The Vancouver Prostate Centre, University of British Columbia, British Columbia, Canada.
authors: Ladan
authors: L
authors: Fazli
authors: Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Malmö, Sweden.
authors: Margareta
authors: M
authors: Persson
authors: Department of Medical Biochemistry and Biophysics, Molecular Infection Medicine Sweden (MIMS), Nordic EMBL Partnership, University of Umeå, Umeå, Sweden.
authors: Lisette
authors: L
authors: Marjavaara
authors: Prostate Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway.
authors: Alfonso
authors: A
authors: Urbanucci
authors: Institute of Biosciences and Medical Technology, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors: Kirsi M
authors: KM
authors: Kaukoniemi
authors: The Vancouver Prostate Centre, University of British Columbia, British Columbia, Canada.
authors: Paul S
authors: PS
authors: Rennie
authors: Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Malmö, Sweden.
authors: Yvonne
authors: Y
authors: Ceder
authors: Department of Medical Biochemistry and Biophysics, Molecular Infection Medicine Sweden (MIMS), Nordic EMBL Partnership, University of Umeå, Umeå, Sweden.
authors: Andrei
authors: A
authors: Chabes
authors: Institute of Biosciences and Medical Technology, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors: Tapio
authors: T
authors: Visakorpi
authors: Prostate Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway.|Department of Cancer Prevention, Oslo University Hospital, Oslo, Norway.|Department of Urology, Oslo University Hospital, Oslo, Norway.
authors: Ian G
authors: IG
authors: Mills
mesh_terms: D015153:Blotting, Western; D002466:Cell Nucleolus / Q000473:pathology*; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007168:IMP Dehydrogenase / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: C410798:AR protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011687:Purines; D011944:Receptors, Androgen; D007168:IMP Dehydrogenase; C501687:IMPDH2 protein, human
keywords: cancer; metabolism; nucleotide; prostate; transcription