Ornithine decarboxylase is sufficient for prostate tumorigenesis via androgen receptor signaling Journal Article

Authors: Shukla-Dave, A.; Castillo-Martin, M.; Chen, M.; Lobo, J.; Gladoun, N.; Collazo-Lorduy, A.; Khan, F. M.; Ponomarev, V.; Yi, Z.; Zhang, W.; Pandolfi, P. P.; Hricak, H.; Cordon-Cardo, C.
Article Title: Ornithine decarboxylase is sufficient for prostate tumorigenesis via androgen receptor signaling
Abstract: Increased polyamine synthesis is known to play an important role in prostate cancer. We aimed to explore its functional significance in prostate tumor initiation and its link to androgen receptor (AR) signaling. For this purpose, we generated a new cell line derived from normal epithelial prostate cells (RWPE-1) with overexpression of ornithine decarboxylase (ODC) and used it for in vitro and in vivo experiments. We then comprehensively analyzed the expression of the main metabolic enzymes of the polyamine pathway and spermine abundance in 120 well-characterized cases of human prostate cancer and high-grade prostate intraepithelial neoplasia (HGPIN). Herein, we show that the ODC-overexpressing prostate cells underwent malignant transformation, revealing that ODC is sufficient for de novo tumor initiation in 94% of injected mice. This oncogenic capacity was acquired through alteration of critical signaling networks, including AR, EIF2, and mTOR/MAPK. RNA silencing experiments revealed the link between AR signaling and polyamine metabolism. Human prostate cancers consistently demonstrated up-regulation of the main polyamine enzymes analyzed (ODC, polyamine oxidase, and spermine synthase) and reduction of spermine. This phenotype was also dominant in HGPIN, rendering it a new biomarker of malignant transformation. In summary, we report that ODC plays a key role in prostate tumorigenesis and that the polyamine pathway is altered as early as HGPIN. © 2016 American Society for Investigative Pathology
Journal Title: American Journal of Pathology
Volume: 186
Issue: 12
ISSN: 0002-9440
Publisher: Elsevier Science, Inc.  
Date Published: 2016-12-01
Start Page: 3131
End Page: 3145
Language: English
DOI: 10.1016/j.ajpath.2016.08.021
PROVIDER: scopus
PUBMED: 27770613
PMCID: PMC5225291
Notes: Article -- Export Date: 6 December 2016 -- Source: Scopus
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MSK Authors
  1. Hedvig Hricak
    330 Hricak
  2. Amita Dave
    80 Dave
  3. Jose Manuel Lobo
    12 Lobo