title: Ectopic expression of the heterotrimeric G15 protein in pancreatic carcinoma and its potential in cancer signal transduction.
abstract: G15 is a heterotrimeric G protein selectively expressed in immature cell lineages in adult tissues that feature higher cell renewal potential. It promiscuously couples a wide variety of G protein-coupled receptors (GPCRs) to phospholipase C. Intriguingly, G15 is poorly affected by GPCR desensitization. We show here that G15 α-subunit (Gα15) supports sustained stimulation of PKD1 by a constitutively desensitized GPCR co-transfected over a negative cell background. Based on the fact that PKD1 is a multifunctional protein kinase activated by PKC and known for promoting oncogenic signaling, we hypothesized that, if expressed out of its natural cell context, G15 might promote tumor growth. A screening for Gα15 mRNA expression pointed to pancreatic carcinoma among different human cancer cell types and revealed significant expression in human tumor biopsies xenografted in mice. In addition, G15 ectopic presence could functionally contribute to the transformation process since siRNA-induced depletion of Gα15 in pancreatic carcinoma cell lines dramatically inhibited anchorage-independent growth and resistance to the lack of nutrients. Altogether, our findings suggest that G15 supports tumorigenic signaling in pancreas and hence it may be considered as a novel potential target for the therapy of this form of cancer.
authors.affiliation: Laboratory of Translational Surgery, University Laboratories of Medical Research (LURM), University of Verona, 37134 Verona, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Giovinazzo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Malpeli
authors.forename: Sara
authors.initials: S
authors.lastname: Zanini
authors.forename: Marco
authors.initials: M
authors.lastname: Parenti
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
authors.forename: Marco
authors.initials: M
authors.lastname: Colombatti
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Valenti
authors.forename: Luca
authors.initials: L
authors.lastname: Dalle Carbonare
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: James
authors.initials: J
authors.lastname: Sinnett-Smith
authors.forename: Enrique
authors.initials: E
authors.lastname: Rozengurt
authors.forename: Claudio
authors.initials: C
authors.lastname: Bassi
authors.forename: Giulio
authors.initials: G
authors.lastname: Innamorati
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000378:metabolism; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D050396:TRPP Cation Channels; D025521:Tumor Suppressor Proteins; C473448:RBM5 protein, human