title: Targeting GIPC/synectin in pancreatic cancer inhibits tumor growth.
abstract: OBJECTIVE
  Various studies have shown the importance of the GAIP interacting protein, COOH-terminus (GIPC, also known as Synectin) as a central adaptor molecule in different signaling pathways and as an important mediator of receptor stability. GIPC/Synectin is associated with different growth-promoting receptors such as insulin-like growth factor receptor I (IGF-IR) and integrins. These interactions were mediated through its PDZ domain. GIPC/Synectin has been shown to be overexpressed in pancreatic and breast cancer. The goal of this study was to show the importance of GIPC/Synectin in pancreatic cancer growth and to evaluate a possible therapeutic strategy by using a GIPC-PDZ domain inhibitor. Furthermore, the effect of targeting GIPC on the IGF-I receptor as one of its associated receptors was tested.
  
  
  METHODS
  The in vivo effects of GIPC/Synectin knockdown were studied after lentiviral transduction of luciferase-expressing pancreatic cancer cells with short hairpin RNA against GIPC/Synectin. Additionally, a GIPC-PDZ--targeting peptide was designed. This peptide was tested for its influence on pancreatic cancer growth in vitro and in vivo.
  
  
  RESULTS
  Knockdown of GIPC/Synectin led to a significant inhibition of pancreatic adenocarcinoma growth in an orthotopic mouse model. Additionally, a cell-permeable GIPC-PDZ inhibitor was able to block tumor growth significantly without showing toxicity in a mouse model. Targeting GIPC was accompanied by a significant reduction in IGF-IR expression in pancreatic cancer cells.
  
  
  CONCLUSIONS
  Our findings show that targeting GIPC/Synectin and its PDZ domain inhibits pancreatic carcinoma growth and is a potential strategy for therapeutic intervention of pancreatic cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Muders
authors.forename: Pawan K
authors.initials: PK
authors.lastname: Vohra
authors.forename: Shamit K
authors.initials: SK
authors.lastname: Dutta
authors.forename: Enfeng
authors.initials: E
authors.lastname: Wang
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: D Gomika
authors.initials: DG
authors.lastname: Udugamasooriya
authors.forename: Adnan
authors.initials: A
authors.lastname: Memic
authors.forename: Chamila N
authors.initials: CN
authors.lastname: Rupasinghe
authors.forename: Chamila N
authors.initials: CN
authors.lastname: Rupashinghe
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Baretton
authors.forename: Daniela E
authors.initials: DE
authors.lastname: Aust
authors.forename: Silke
authors.initials: S
authors.lastname: Langer
authors.forename: Kaustubh
authors.initials: K
authors.lastname: Datta
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
authors.forename: Mark R
authors.initials: MR
authors.lastname: Spaller
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology*; D054731:PDZ Domains / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C492009:GIPC1 protein, human; D016023:Integrins; D009842:Oligopeptides; D017526:Receptor, IGF Type 1