TY - JOUR
T1 - Targeting GIPC/synectin in pancreatic cancer inhibits tumor growth
AU - Muders, Michael H.
AU - Vohra, Pawan K.
AU - Dutta, Shamit K.
AU - Wang, Enfeng
AU - Ikeda, Yasuhiro
AU - Wang, Ling
AU - Udugamasooriya, D. Gomika
AU - Memic, Adnan
AU - Rupashinghe, Chamila N.
AU - Baretton, Gustavo B.
AU - Aust, Daniela E.
AU - Langer, Silke
AU - Datta, Kaustubh
AU - Simons, Michael
AU - Spaller, Mark R.
AU - Mukhopadhyay, Debabrata
PY - 2009/6/15
Y1 - 2009/6/15
N2 - 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 blocktu mor 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.
AB - 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 blocktu mor 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.
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U2 - 10.1158/1078-0432.CCR-08-2837
DO - 10.1158/1078-0432.CCR-08-2837
M3 - Article
C2 - 19509165
AN - SCOPUS:67449138838
SN - 1078-0432
VL - 15
SP - 4095
EP - 4103
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 12
ER -