A Novel Interplay between Rap1 and PKA Regulates Induction of Angiogenesis in Prostate Cancer |
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| Authors: | Jyotsana Menon Robert C Doebele Suzana Gomes Elena Bevilacqua Katie M Reindl Marsha Rich Rosner |
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| Institution: | 1. Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, United States of America.; 2. School of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.; 3. Department of Biological Sciences, North Dakota State University, Fargo, North Dakota, United States of America.; Rush University Medical Center, United States of America, |
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| Abstract: | Angiogenesis inhibition is an important therapeutic strategy for advanced stage prostate cancer. Previous work from our laboratory showed that sustained stimulation of Rap1 by 8-pCPT-2''-O-Me-cAMP (8CPT) via activation of Epac, a Rap1 GEF, or by expression of a constitutively active Rap1 mutant (cRap1) suppresses endothelial cell chemotaxis and subsequent angiogenesis. When we tested this model in the context of a prostate tumor xenograft, we found that 8CPT had no significant effect on prostate tumor growth alone. However, in cells harboring cRap1, 8CPT dramatically inhibited not only prostate tumor growth but also VEGF expression and angiogenesis within the tumor microenvironment. Subsequent analysis of the mechanism revealed that, in prostate tumor epithelial cells, 8CPT acted via stimulation of PKA rather than Epac/Rap1. PKA antagonizes Rap1 and hypoxic induction of 1α protein expression, VEGF production and, ultimately, angiogenesis. Together these findings provide evidence for a novel interplay between Rap1, Epac, and PKA that regulates tumor-stromal induction of angiogenesis. |
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