Abstract
Prognosis for patients with early stage kidney cancer has improved, but the treatment options for patients with locally advanced disease and metastasis remain few. Understanding the molecular mechanisms that regulate invasion and metastasis is critical for developing successful therapies to treat these patients. Proinflammatory prostaglandin E(2) plays an important role in cancer initiation and progression via activation of cognate EP receptors that belong to the superfamily of G protein-coupled receptors. Here we report that prostaglandin E(2) promotes renal cancer cell invasion through a signal transduction pathway that encompasses EP4 and small GTPase Rap. Inactivation of Rap signaling with Rap1GAP, like inhibition of EP4 signaling with ligand antagonist or knockdown with shRNA, reduces the kidney cancer cell invasion. Human kidney cells evidence increased EP4 and decreased Rap1GAP expression levels in the malignant compared with benign samples. These results support the idea that targeted inhibition of EP4 signaling and restoration of Rap1GAP expression constitute a new strategy to control kidney cancer progression.
Highlights
Kidney tumor mass is sustained by the release of circulating and locally produced factors acting through cellular receptors that can switch the susceptible quiescent kidney cells to an activated state
Majority of kidney cancer-related deaths result from cancer metastasis to distal organs and the prognosis of patients with metastatic disease is poor with a median survival of 10 months [4, 42, 43]
Surgery is highly effective for the treatment of localized low-grade Renal cell carcinoma (RCC) [43], current management options of patients diagnosed with locally advanced or metastatic kidney cancer are not curative, reinforcing the need to identify mechanisms involved in kidney cancer initiation, survival, and metastasis as a prerequisite for discovering effective therapeutics
Summary
Kidney tumor mass is sustained by the release of circulating and locally produced factors acting through cellular receptors that can switch the susceptible quiescent kidney cells to an activated state. PGE2 exerts its effects on target cells through activation of cognate receptors named EP1, EP2, EP3, and EP4 [6, 17] that belong to the superfamily of G protein-coupled receptors. The results show that PGE2 promotes kidney cancer cell invasion through activation of EP4 and small GTPase Rap proteins. EP4 protein expression is increased in malignant compared with benign human kidney cells and inversely correlates with Rap1GAP protein expression. These studies identify EP4 and Rap1GAP proteins as positive and negative regulators, respectively, of kidney cancer cell invasion, and suggest their utility as prognostic markers and therapeutic targets to limit patient morbidity and mortality
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