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Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). (Andrei Chabes)
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2015 (engelsk)Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 14, s. 12587-12602Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
2015. Vol. 6, nr 14, s. 12587-12602
Emneord [en]
prostate, cancer, nucleotide, transcription, metabolism
HSV kategori
Identifikatorer
URN: urn:nbn:se:umu:diva-101879ISI: 000359008200062PubMedID: 25869206OAI: oai:DiVA.org:umu-101879DiVA, id: diva2:805384
Tilgjengelig fra: 2015-04-15 Laget: 2015-04-15 Sist oppdatert: 2018-06-07bibliografisk kontrollert

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