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

Barfeld, Stefan J; Fazli, Ladan; Persson, Margareta LU ; Marjavaara, Lisette; Urbanucci, Alfonso; Kaukoniemi, Kirsi M; Rennie, Paul S; Ceder, Yvonne LU ; Chabes, Andrei and Visakorpi, Tapio, et al. (2015) In Oncotarget 6(14). p.12587-12602
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... (More)
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. (Less)
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publication status
published
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in
Oncotarget
volume
6
issue
14
pages
12587 - 12602
publisher
Impact Journals, LLC
external identifiers
  • pmid:25869206
  • wos:000359008200062
  • scopus:84930025578
ISSN
1949-2553
DOI
10.18632/oncotarget.3494
language
English
LU publication?
yes
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db3ca0fd-051d-4b94-b270-3984a7c5a66f (old id 5342006)
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http://www.ncbi.nlm.nih.gov/pubmed/25869206?dopt=Abstract
date added to LUP
2015-05-05 20:35:00
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2017-09-24 03:53:40
@article{db3ca0fd-051d-4b94-b270-3984a7c5a66f,
  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.},
  author       = {Barfeld, Stefan J and Fazli, Ladan and Persson, Margareta and Marjavaara, Lisette and Urbanucci, Alfonso and Kaukoniemi, Kirsi M and Rennie, Paul S and Ceder, Yvonne and Chabes, Andrei and Visakorpi, Tapio and Mills, Ian G},
  issn         = {1949-2553},
  language     = {eng},
  number       = {14},
  pages        = {12587--12602},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer.},
  url          = {http://dx.doi.org/10.18632/oncotarget.3494},
  volume       = {6},
  year         = {2015},
}