- Clin Cancer Res. 2009 Jun 15;15(12):4095-103. Epub 2009 Jun 9.
Targeting GIPC/synectin in pancreatic cancer inhibits tumor growth.
Muders MH, Vohra PK, Dutta SK, Wang E, Ikeda Y, Wang L, Udugamasooriya DG, Memic A, Rupashinghe CN, Baretton GB, Aust DE, Langer S, Datta K, Simons M, Spaller MR, Mukhopadhyay D.
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
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
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.