title: The progenitor cell marker NG2/MPG promotes chemoresistance by activation of integrin-dependent PI3K/Akt signaling.
abstract: Chemoresistance represents a major problem in the treatment of many malignancies. Overcoming this obstacle will require improved understanding of the mechanisms responsible for this phenomenon. The progenitor cell marker NG2/melanoma proteoglycan (MPG) is aberrantly expressed by various tumors, but its role in cell death signaling and its potential as a therapeutic target are largely unexplored. We have assessed cytotoxic drug-induced cell death in glioblastoma spheroids from 15 patients, as well as in five cancer cell lines that differ with respect to NG2/MPG expression. The tumors were treated with doxorubicin, etoposide, carboplatin, temodal, cisplatin and tumor necrosis factor (TNF)alpha. High NG2/MPG expression correlated with multidrug resistance mediated by increased activation of alpha3beta1 integrin/PI3K signaling and their downstream targets, promoting cell survival. NG2/MPG knockdown with shRNAs incorporated into lentiviral vectors attenuated beta1 integrin signaling revealing potent antitumor effects and further sensitized neoplastic cells to cytotoxic treatment in vitro and in vivo. Thus, as a novel regulator of the antiapoptotic response, NG2/MPG may represent an effective therapeutic target in several cancer subtypes.
authors.affiliation: Norlux Neuro-Oncology Group, Department of Biomedicine, University of Bergen, Bergen, Norway. martha.chekenya@biomed.uib.no
authors.forename: M
authors.initials: M
authors.lastname: Chekenya
authors.forename: C
authors.initials: C
authors.lastname: Krakstad
authors.forename: A
authors.initials: A
authors.lastname: Svendsen
authors.forename: I A
authors.initials: IA
authors.lastname: Netland
authors.forename: V
authors.initials: V
authors.lastname: Staalesen
authors.forename: B B
authors.initials: BB
authors.lastname: Tysnes
authors.forename: F
authors.initials: F
authors.lastname: Selheim
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: P Ø
authors.initials: PØ
authors.lastname: Sakariassen
authors.forename: T
authors.initials: T
authors.lastname: Sandal
authors.forename: P E
authors.initials: PE
authors.lastname: Lønning
authors.forename: T
authors.initials: T
authors.lastname: Flatmark
authors.forename: P Ø
authors.initials: PØ
authors.lastname: Enger
authors.forename: R
authors.initials: R
authors.lastname: Bjerkvig
authors.forename: M
authors.initials: M
authors.lastname: Sioud
authors.forename: W B
authors.initials: WB
authors.lastname: Stallcup
mesh_terms: D000941:Antigens / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016023:Integrins / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011509:Proteoglycans / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D016023:Integrins; D019869:Phosphatidylinositol 3-Kinases; D011509:Proteoglycans; D051057:Proto-Oncogene Proteins c-akt; D014409:Tumor Necrosis Factor-alpha; D000099216:Chondroitin Sulfate Proteoglycan 4