Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer
// Stefan J. Barfeld 1 , Ladan Fazli 2 , Margareta Persson 3 , Lisette Marjavaara 4 , Alfonso Urbanucci 1 , Kirsi M. Kaukoniemi 5 , Paul S. Rennie 2 , Yvonne Ceder 3 , Andrei Chabes 4 , Tapio Visakorpi 5 , Ian G. Mills 1, 6, 7 1 Prostate Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway 2 The Vancouver Prostate Centre, University of British Columbia, Canada 3 Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Malmö, Sweden 4 Department of Medical Biochemistry and Biophysics, Molecular Infection Medicine Sweden (MIMS), Nordic EMBL Partnership, University of Umeå, Umeå, Sweden 5 Institute of Biosciences and Medical Technology, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland 6 Department of Cancer Prevention, Oslo University Hospital, Oslo, Norway 7 Department of Urology, Oslo University Hospital, Oslo, Norway Correspondence to: Ian G. Mills, e-mail: ian.mills@ncmm.uio.no Stefan J. Barfeld, e-mail: stefan.barfeld@ncmm.uio.no Keywords: prostate, cancer, nucleotide, transcription, metabolism Received: September 28, 2014 Accepted: March 07, 2015 Published: April 01, 2015 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.