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. We analyzed 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Pal
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth and Norris Cotton Cancer Center, Lebanon, New Hampshire.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Pletnev
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Shamit K
authors.initials: SK
authors.lastname: Dutta
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Enfeng
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth and Norris Cotton Cancer Center, Lebanon, New Hampshire.
authors.forename: Ruizhi
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, Council for Scientific and Industrial Research, New Delhi, India.
authors.forename: Aradhita
authors.initials: A
authors.lastname: Baral
authors.affiliation: G.N.R. Knowledge Center for Genome Informatics, Institute of Genomics and Integrative Biology, Council for Scientific and Industrial Research, New Delhi, India.
authors.forename: Vinod Kumar
authors.initials: VK
authors.lastname: Yadav
authors.affiliation: G.N.R. Knowledge Center for Genome Informatics, Institute of Genomics and Integrative Biology, Council for Scientific and Industrial Research, New Delhi, India.
authors.forename: Suruchi
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: Department of Biochemistry, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Soundararajan
authors.initials: S
authors.lastname: Krishnaswamy
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota. Department of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Alkharfy
authors.affiliation: Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, Council for Scientific and Industrial Research, New Delhi, India. G.N.R. Knowledge Center for Genome Informatics, Institute of Genomics and Integrative Biology, Council for Scientific and Industrial Research, New Delhi, India.
authors.forename: Shantanu
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth and Norris Cotton Cancer Center, Lebanon, New Hampshire.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Spaller
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota. mukhopadhyay.debabrata@mayo.edu.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D000071063:Endoglin; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D010455:Peptides / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011897:Random Allocation; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C492009:GIPC1 protein, human; D008024:Ligands; D010455:Peptides; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D003841:Deoxycytidine; D000093542:Gemcitabine