BERKELEY, CA (UroToday.com) - This article describes a novel mechanism for regulating angiogenesis in prostate cancer. The results highlight an interplay between activated Rap1 and PKA that regulates production of the pro-angiogenic factor VEGF in prostate tumor cells. Our previous studies showed that Epac activation of Rap1 in endothelial cells induced thrombospondin 1 (TSP1), an inhibitor of angiogenesis. Activation of these two pathways in prostate tumor and stroma, respectively, can lead to coordinated suppression of angiogenesis.
There are still a few aspects of the mechanism that remain to be resolved. Although we used the cAMP analogue 8CPT to activate Rap1 via Epac in both tumor and endothelial cells, the effector of VEGF inhibition in the prostate tumor cells was PKA; thus, 8CPT antagonized Rap1 induction of VEGF. Since 8CPT is believed to be a specific activator of Epac (which activates Rap1) and not PKA, this result was surprising. However, further studies suggested that the mechanism of PKA activation was indirect since the effect required hours of treatment. Depletion of Epac1 or 2 had no significant effect, but we cannot rule out a role for the residual Epac that remained in the cell. Alternatively, cAMP has other targets that might respond to 8CPT. However, we did show that the mechanism is not due to simple GTPase inactivation of Rap1.These results suggest that drug treatments involving the cAMP pathway can coordinately inhibit angiogenesis via PKA activation in prostate cells and Epac/Rap1 activation in endothelial cells.
The process of angiogenesis is complex, and the regulating factors and mediators of the process are various. To date, clinical success of anti-angiogenesis therapy for prostate cancer has been disappointing. Phase III trials of anti-angiogenesis agents used against hormone-refractory metastatic prostate cancers have been negative. The use of bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF-A), in combination with docetaxel and prednisone demonstrated an improvement in progression-free survival, but no overall survival benefit. Aflibercept, also an inhibitor of vascular endothelial growth factors (VEGF-A, VEGF-B and placental growth factor), is currently being studied. Endothelin-1 receptor antagonists, zibotentan (ZD5054), and atrasentan have been tested in phase III studies, and, disappointingly, did not demonstrate any survival benefit despite the fact endothelin-1 is abundant in prostate cancer and involved in prostate cancer cell proliferation, invasion, and angiogenesis. An oral anti-angiogenic drug, tasquinimod, which regulates suppressive and pro-angiogenic cells in the tumor microenvironment, has demonstrated clinically modest improvements in progression-free survival in phase II studies.
The results in this article demonstrate the different roles mediators play in the process of angiogenesis. In addition to defining other mediators of angiogenesis as targets of therapy, such investigations may help guide rational combination agent therapies. Although activators of PKA pose other potential hazards such as perturbations in cardiac function, induction of cAMP through more physiological regulators might prove useful as a therapeutic strategy.
Written by:
Eugene Choia and Marsha Rich Rosnerb as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
aDept. of Surgery and bBen May Dept. for Cancer Research, University of Chicago, Chicago, IL USA 60637
A novel interplay between Rap1 and PKA regulates induction of angiogenesis in prostate cancer - Abstract
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