The progenitor cell marker NG2/MPG promotes chemoresistance by activation of integrin-dependent PI3K/Akt signaling

M. Chekenya*, C. Krakstad, A. Svendsen, I. A. Netland, V. Staalesen, B. B. Tysnes, F. Selheim, J. Wang, P. Sakariassen, T. Sandal, P. E. Lønning, T. Flatmark, P. Enger, R. Bjerkvig, M. Sioud, W. B. Stallcup

*Corresponding author for this work

    Research output: Contribution to journalArticleResearchpeer-review

    122 Citations (Scopus)

    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)α. High NG2/MPG expression correlated with multidrug resistance mediated by increased activation of α3Β1 integrin/PI3K signaling and their downstream targets, promoting cell survival. NG2/MPG knockdown with shRNAs incorporated into lentiviral vectors attenuated Β1 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.

    Original languageEnglish
    Pages (from-to)5182-5194
    Number of pages13
    JournalOncogene
    Volume27
    Issue number39
    DOIs
    Publication statusPublished - 4 Sept 2008

    Keywords

    • Apoptosis
    • Chemoresistance
    • Integrin
    • NG2/MPG

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