Journal
ONCOGENE
Volume 27, Issue 39, Pages 5182-5194Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.157
Keywords
apoptosis; chemoresistance; integrin; NG2/MPG
Funding
- The Norwegian Cancer Society
- The Bergen Translational Research Group
- Familien Blix Fond
- University of Bergen
- National Institutes of Health [RO1 CA95287]
- Sixth EU Framework Programme
- Helse-Vest
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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 alpha 3 beta 1 integrin/PI3K signaling and their downstream targets, promoting cell survival. NG2/MPG knockdown with shRNAs incorporated into lentiviral vectors attenuated beta 1 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.
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