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.
The American journal of pathology. 2016 Oct 19 [Epub ahead of print]
Amita Shukla-Dave, Mireia Castillo-Martin, Ming Chen, Jose Lobo, Nataliya Gladoun, Ana C Lorduy, Faisal M Khan, Vladimir Ponomarev, Zhengzi Yi, Weijia Zhang, Pier P Pandolfi, Hedvig Hricak, Carlos Cordon-Cardo
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., Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pathology, Champalimaud Centre for the Unknown, Lisbon, Portugal., Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts., Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York., Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York., Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York; Spanish Society of Medical Oncology, Madrid, Spain., Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York., Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: .