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.
authors: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Amita
authors: A
authors: Shukla-Dave
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pathology, Champalimaud Centre for the Unknown, Lisbon, Portugal.
authors: Mireia
authors: M
authors: Castillo-Martin
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors: Ming
authors: M
authors: Chen
authors: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Jose
authors: J
authors: Lobo
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Nataliya
authors: N
authors: Gladoun
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York; Spanish Society of Medical Oncology, Madrid, Spain.
authors: Ana
authors: A
authors: Collazo-Lorduy
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Faisal M
authors: FM
authors: Khan
authors: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Vladimir
authors: V
authors: Ponomarev
authors: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Zhengzi
authors: Z
authors: Yi
authors: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Weijia
authors: W
authors: Zhang
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors: Pier P
authors: PP
authors: Pandolfi
authors: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Hedvig
authors: H
authors: Hricak
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: carlos.cordon-cardo@mssm.edu.
authors: Carlos
authors: C
authors: Cordon-Cardo
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D063646:Carcinogenesis; D002460:Cell Line; D015331:Cohort Studies; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D011467:Prostate / Q000201:enzymology / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D000097667:Polyamine Oxidase
chemical_list: D009955:Ornithine Decarboxylase; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D011944:Receptors, Androgen; D000097667:Polyamine Oxidase