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

8 Citations (Scopus)

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

Fingerprint

Protein C
Pancreatic Neoplasms
Growth
gemcitabine
RNA Interference
PDZ Domains
Lipopeptides
Endoglin
Neoplasms
Gastrointestinal Stromal Tumors
Heterografts
Disulfides
Ovarian Neoplasms
Blood Vessels
Endothelial Cells
Breast Neoplasms
Ligands
Phenotype
Cell Line
Peptides

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Inhibition of endoglin-GIPC interaction inhibits pancreatic cancer cell growth. / Pal, Krishnendu; Pletnev, Alexandre A.; Dutta, Shamit K.; Wang, Enfeng; Zhao, Ruizhi; Baral, Aradhita; Yadav, Vinod Kumar; Aggarwal, Suruchi; Krishnaswamy, Soundararajan; Alkharfy, Khalid M.; Chowdhury, Shantanu; Spaller, Mark R.; Mukhopadhyay, Debabrata.

In: Molecular Cancer Therapeutics, Vol. 13, No. 10, 14.08.2014, p. 2264-2275.

Research output: Contribution to journalArticle

Pal, K, Pletnev, AA, Dutta, SK, Wang, E, Zhao, R, Baral, A, Yadav, VK, Aggarwal, S, Krishnaswamy, S, Alkharfy, KM, Chowdhury, S, Spaller, MR & Mukhopadhyay, D 2014, 'Inhibition of endoglin-GIPC interaction inhibits pancreatic cancer cell growth', Molecular Cancer Therapeutics, vol. 13, no. 10, pp. 2264-2275. https://doi.org/10.1158/1535-7163.MCT-14-0291
Pal, Krishnendu ; Pletnev, Alexandre A. ; Dutta, Shamit K. ; Wang, Enfeng ; Zhao, Ruizhi ; Baral, Aradhita ; Yadav, Vinod Kumar ; Aggarwal, Suruchi ; Krishnaswamy, Soundararajan ; Alkharfy, Khalid M. ; Chowdhury, Shantanu ; Spaller, Mark R. ; Mukhopadhyay, Debabrata. / Inhibition of endoglin-GIPC interaction inhibits pancreatic cancer cell growth. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 10. pp. 2264-2275.
@article{f02a1a668c0740ed98875cb3f1644e71,
title = "Inhibition of endoglin-GIPC interaction inhibits pancreatic cancer cell growth",
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.",
author = "Krishnendu Pal and Pletnev, {Alexandre A.} and Dutta, {Shamit K.} and Enfeng Wang and Ruizhi Zhao and Aradhita Baral and Yadav, {Vinod Kumar} and Suruchi Aggarwal and Soundararajan Krishnaswamy and Alkharfy, {Khalid M.} and Shantanu Chowdhury and Spaller, {Mark R.} and Debabrata Mukhopadhyay",
year = "2014",
month = "8",
day = "14",
doi = "10.1158/1535-7163.MCT-14-0291",
language = "English (US)",
volume = "13",
pages = "2264--2275",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=84926640149&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84926640149&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-14-0291

DO - 10.1158/1535-7163.MCT-14-0291

M3 - Article

C2 - 25125675

AN - SCOPUS:84926640149

VL - 13

SP - 2264

EP - 2275

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 10

ER -