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

Stefan J Barfeld, Ladan Fazli, Margareta Persson, Lisette Marjavaara, Alfonso Urbanucci, Kirsi M Kaukoniemi, Paul S Rennie, Yvonne Ceder, Andrei Chabes, Tapio Visakorpi, Ian G Mills

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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.

Original languageEnglish
Pages (from-to)12587-602
Number of pages16
JournalOncotarget
Volume6
Issue number14
Early online date30 Mar 2015
DOIs
Publication statusPublished - 20 May 2015

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    Barfeld, S. J., Fazli, L., Persson, M., Marjavaara, L., Urbanucci, A., Kaukoniemi, K. M., Rennie, P. S., Ceder, Y., Chabes, A., Visakorpi, T., & Mills, I. G. (2015). Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer. Oncotarget, 6(14), 12587-602. https://doi.org/10.18632/oncotarget.3494