title: Interfering with the interaction between ErbB1, nucleolin and Ras as a potential treatment for glioblastoma.
abstract: The three oncogenes, ErbB receptors, Ras proteins and nucleolin may contribute to malignant transformation. Previously, we demonstrated that nucleolin could bind both Ras protein and ErbB receptors. We also showed that the crosstalk between the three proteins facilitates anchorage independent growth and tumor growth in nude mice, and that inhibition of this interaction in prostate and colon cancer cells reduces tumorigenicity. In the present study, we show that treatment with Ras and nucleolin inhibitors reduces the oncogenic effect induced by ErbB1 receptor in U87-MG cells. This combined treatment enhances cell death, reduces cell proliferation and cell migration. Moreover, we demonstrate a pivotal role of nucleolin in ErbB1 activation by its ligand. Nucleolin inhibitor prevents EGF-induced receptor activation and its downstream signaling followed by reduced proliferation. Furthermore, inhibition of Ras by Salirasib (FTS), mainly reduces cell viability and motility. The combined treatment, which targets both Ras and nucleolin, additively reduces tumorigenicity both in vitro and in vivo. These results suggest that targeting both nucleolin and Ras may represent an additional opportunity for inhibiting cancers, including glioblastoma, that are driven by these oncogenes.
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel. Australian Regenerative Medicine Institute, Monash University, Australia. These authors contributed equally to this work.
authors.forename: Yona
authors.initials: Y
authors.lastname: Goldshmit
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel. These authors contributed equally to this work.
authors.forename: Sari Schokoroy
authors.initials: SS
authors.lastname: Trangle
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Pinkas-Kramarski
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D052157:Aptamers, Nucleotide; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D005204:Farnesol / Q000008:administration & dosage / Q000031:analogs & derivatives; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008819:Mice, Nude; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk; D012459:Salicylates / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097796:Nucleolin
chemical_list: D052157:Aptamers, Nucleotide; D066246:ErbB Receptors; D005204:Farnesol; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D012459:Salicylates; D018631:ras Proteins; D000097796:Nucleolin; C513936:AGRO 100; C093323:farnesylthiosalicylic acid; C512478:EGFR protein, human