title: Prostaglandin E2 regulates renal cell carcinoma invasion through the EP4 receptor-Rap GTPase signal transduction pathway.
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.
authors.affiliation: Department of Pathology, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Wu
authors.forename: Yushan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Nicole
authors.initials: N
authors.lastname: Frilot
authors.forename: Jae I
authors.initials: JI
authors.lastname: Kim
authors.forename: Wan-Ju
authors.initials: WJ
authors.lastname: Kim
authors.forename: Yehia
authors.initials: Y
authors.lastname: Daaka
mesh_terms: D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction
chemical_list: D020690:GTPase-Activating Proteins; D009363:Neoplasm Proteins; C484658:RAP1GAP protein, human; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone