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.
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.
Authors: Tal Varsano; Meng-Qiu Dong; Ingrid Niesman; Hyacynth Gacula; Xiaojing Lou; Tianlin Ma; Joseph R Testa; John R Yates; Marilyn G Farquhar Journal: Mol Cell Biol Date: 2006-10-02 Impact factor: 4.272
Authors: Michael H Muders; Shamit K Dutta; Ling Wang; Julie S Lau; Resham Bhattacharya; Thomas C Smyrk; Suresh T Chari; Kaustubh Datta; Debabrata Mukhopadhyay Journal: Cancer Res Date: 2006-11-01 Impact factor: 12.701
Authors: A Singer; Y Deuse; U Koch; T Hölscher; D Pfitzmann; C Jakob; S Hehlgans; G B Baretton; A Rentsch; M Baumann; M H Muders; M Krause Journal: Strahlenther Onkol Date: 2012-11-07 Impact factor: 3.621