TY - JOUR
T1 - Inhibition of endoglin-GIPC interaction inhibits pancreatic cancer cell growth
AU - Pal, Krishnendu
AU - Pletnev, Alexandre A.
AU - Dutta, Shamit K.
AU - Wang, Enfeng
AU - Zhao, Ruizhi
AU - Baral, Aradhita
AU - Yadav, Vinod Kumar
AU - Aggarwal, Suruchi
AU - Krishnaswamy, Soundararajan
AU - Alkharfy, Khalid M.
AU - Chowdhury, Shantanu
AU - Spaller, Mark R.
AU - Mukhopadhyay, Debabrata
N1 - Publisher Copyright:
©2014 AACR.
PY - 2014/8/14
Y1 - 2014/8/14
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-14-0291
DO - 10.1158/1535-7163.MCT-14-0291
M3 - Article
C2 - 25125675
AN - SCOPUS:84926640149
SN - 1535-7163
VL - 13
SP - 2264
EP - 2275
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 10
ER -