PROSTAGLANDIN RECEPTOR REGULATION OF KIDNEY CANCER Renal cell carcinoma is a leading cause of cancer death, and its incidence is steadily increasing at an annual rate of 2.5% across population groups. Approximately one third of patients present with metastatic disease, and the prognosis of such patients is poor with a median survival of ten months. Although surgery is highly effective for the treatment of localized renal cell carcinoma (RCC), treatment options available for patients with metastatic disease are very limited. Hence, understanding the molecular events operating in RCC will help in gaining better insight into the molecular pathogenesis of the cancer and, therefore, open the door to highly specific and effective mechanism-based treatment options for metastatic disease. We have cloned a new line of clear cell RCC (RCC7) that is tumorigenic and metastatic in mice. Gene and protein expression analyses revealed that the RCC7 cells possess altered levels of G protein-coupled receptor signaling intermediates, including increased expression of the ? subunits of Gs and Gq, and EP4 subtype of prostaglandin E2 (PGE2) receptor, and decreased expression of the small GTPase inactivator Rap1GAP, in comparison to normal epithelial kidney cells. Treatment with PGE2 promoted the Rap1-mediated RCC7 cell invasion, and the rescued expression of Rap1GAP attenuated the PGE2- mediated cell invasion in vitro and metastasis in animals. Based on these results, and taking into account previous knowledge, we hypothesize that unregulated expression/function of the EP4 is involved in RCC invasion.
The specific aims of this application are:  To profile EP receptors expression and to establish the EP subtype(s) that mediate the RCC cell invasion in vitro using available EP receptor-specific agonists and antagonists, and EP receptor knockdown with RNAi,  To determine the molecular mechanisms responsible for the PGE2-mediated RCC cell invasion with special emphasis on small GTPase Rap1 activation, and  To determine the role of EP4 and Rap1 signaling in the in vivo growth and metastasis of RCC tumors using animal model systems. The successful conclusion of these studies may identify EP4 and Rap as novel drug targets effective for the treatment of advanced kidney malignancies. Narrative: Patients with metastatic renal cell carcinoma (RCC) have limited treatment options, and mechanisms involved in the initiation and progression of RCC are not fully known. We have identified EP4 and Rap as mediators of invasion and metastasis of RCC cells. Targeted disruption of EP4 signaling and inactivation of Rap may provide a window of opportunity to interfere with progression of kidney cancer to currently incurable advanced disease.
|Ma, Xiaojie; Espana-Serrano, Laura; Kim, Wan-ju et al. (2014) ?Arrestin1 regulates the guanine nucleotide exchange factor RasGRF2 expression and the small GTPase Rac-mediated formation of membrane protrusion and cell motility. J Biol Chem 289:13638-50|
|Eruslanov, Evgeniy; Stoffs, Taryn; Kim, Wan-Ju et al. (2013) Expansion of CCR8(+) inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas. Clin Cancer Res 19:1670-80|
|Li, Z; Zhang, Y; Kim, W J et al. (2013) PGE2 promotes renal carcinoma cell invasion through activated RalA. Oncogene 32:1408-15|
|Kim, Wan-Ju; Gersey, Zachary; Daaka, Yehia (2012) Rap1GAP regulates renal cell carcinoma invasion. Cancer Lett 320:65-71|
|Kim, Jae Il; Chakraborty, Prabir; Wang, Zhimin et al. (2012) G-protein coupled receptor kinase 5 regulates prostate tumor growth. J Urol 187:322-9|
|Zhang, Yushan; Daaka, Yehia (2011) PGE2 promotes angiogenesis through EP4 and PKA C? pathway. Blood 118:5355-64|
|Eruslanov, Evgeniy; Daurkin, Irina; Vieweg, Johannes et al. (2011) Aberrant PGEýýý metabolism in bladder tumor microenvironment promotes immunosuppressive phenotype of tumor-infiltrating myeloid cells. Int Immunopharmacol 11:848-55|
|Wu, Juanjuan; Zhang, Yushan; Frilot, Nicole et al. (2011) Prostaglandin E2 regulates renal cell carcinoma invasion through the EP4 receptor-Rap GTPase signal transduction pathway. J Biol Chem 286:33954-62|
|Kim, Jae Il; Lakshmikanthan, Vijayabaskar; Frilot, Nicole et al. (2010) Prostaglandin E2 promotes lung cancer cell migration via EP4-betaArrestin1-c-Src signalsome. Mol Cancer Res 8:569-77|
|Zhu, Yunjuan; Wu, Yuanjun; Kim, Jae I et al. (2009) Arf GTPase-activating protein AGAP2 regulates focal adhesion kinase activity and focal adhesion remodeling. J Biol Chem 284:13489-96|
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