Inhibition of endoglin-GIPC interaction inhibits pancreatic cancer cell growth

Krishnendu Pal, Alexandre A. Pletnev, Shamit K. Dutta, Enfeng Wang, Ruizhi Zhao, Aradhita Baral, Vinod Kumar Yadav, Suruchi Aggarwal, Soundararajan Krishnaswamy, Khalid M. Alkharfy, Shantanu Chowdhury, Mark R. Spaller, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Endoglin, a 180-kDa disulfide-linked homodimeric transmembrane receptor protein mostly expressed in tumor-associated endothelial cells, is an endogenous binding partner of GAIP-interacting protein, C terminus (GIPC). Endoglin functions as a coreceptor of TβRII that binds TGFβ and is important for vascular development, and consequently has become a compelling target for antiangiogenic therapies. A few recent studies in gastrointestinal stromal tumor (GIST), breast cancer, and ovarian cancer, however, suggest that endoglin is upregulated in tumor cells and is associated with poor prognosis. These findings indicate a broader role of endoglin in tumor biology, beyond angiogenic effects. The goal of our current study is to evaluate the effects of targeting endoglin in pancreatic cancer both in vitro and in vivo. Weanalyzed the antiproliferative effect of both RNAi-based and peptide ligand-based inhibition of endoglin in pancreatic cancer cell lines, the latter yielding a GIPC PDZ domain-targeting lipopeptide with notable antiproliferative activity. We further demonstrated that endoglin inhibition induced a differentiation phenotype in the pancreatic cancer cells and sensitized them against conventional chemotherapeutic drug gemcitabine. Most importantly, we have demonstrated the antitumor effect of both RNAi-based and competitive inhibitor-based blocking of endoglin in pancreatic cancer xenograft models in vivo. To our knowledge, this is the first report exploring the effect of targeting endoglin in pancreatic cancer cells.

Original languageEnglish (US)
Pages (from-to)2264-2275
Number of pages12
JournalMolecular cancer therapeutics
Volume13
Issue number10
DOIs
StatePublished - Aug 14 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Pal, K., Pletnev, A. A., Dutta, S. K., Wang, E., Zhao, R., Baral, A., Yadav, V. K., Aggarwal, S., Krishnaswamy, S., Alkharfy, K. M., Chowdhury, S., Spaller, M. R., & Mukhopadhyay, D. (2014). Inhibition of endoglin-GIPC interaction inhibits pancreatic cancer cell growth. Molecular cancer therapeutics, 13(10), 2264-2275. https://doi.org/10.1158/1535-7163.MCT-14-0291