Targeting GIPC/synectin in pancreatic cancer inhibits tumor growth

Michael H. Muders, Pawan K. Vohra, Shamit K. Dutta, Enfeng Wang, Yasuhiro Ikeda, Ling Wang, D. Gomika Udugamasooriya, Adnan Memic, Chamila N. Rupashinghe, Gustavo B. Baretton, Daniela E. Aust, Silke Langer, Kaustubh Datta, Michael Simons, Mark R. Spaller, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4095-4103
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number12
DOIs
StatePublished - Jun 15 2009

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Muders, M. H., Vohra, P. K., Dutta, S. K., Wang, E., Ikeda, Y., Wang, L., Udugamasooriya, D. G., Memic, A., Rupashinghe, C. N., Baretton, G. B., Aust, D. E., Langer, S., Datta, K., Simons, M., Spaller, M. R., & Mukhopadhyay, D. (2009). Targeting GIPC/synectin in pancreatic cancer inhibits tumor growth. Clinical Cancer Research, 15(12), 4095-4103. https://doi.org/10.1158/1078-0432.CCR-08-2837