Targeting GIPC/synectin in pancreatic cancer inhibits tumor growth. Clin Cancer Res 2009 Jun 15;15(12):4095-103
Date
06/11/2009Pubmed ID
19509165Pubmed Central ID
PMC2731998DOI
10.1158/1078-0432.CCR-08-2837Scopus ID
2-s2.0-67449138838 (requires institutional sign-in at Scopus site) 38 CitationsAbstract
PURPOSE: 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.
EXPERIMENTAL DESIGN: 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.
Author List
Muders MH, Vohra PK, Dutta SK, Wang E, Ikeda Y, Wang L, Udugamasooriya DG, Memic A, Rupasinghe CN, Baretton GB, Aust DE, Langer S, Datta K, Simons M, Spaller MR, Mukhopadhyay DMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAnimals
Antineoplastic Agents
Cell Proliferation
Female
Gene Knockdown Techniques
Humans
Integrins
Mice
Mice, Nude
Oligopeptides
PDZ Domains
Pancreatic Neoplasms
Receptor, IGF Type 1
Signal Transduction