Chekenya M, Krakstad C, Svendsen A, Netland I A, Staalesen V, Tysnes B B, Selheim F, Wang J, Sakariassen P Ø, Sandal T, Lønning P E, Flatmark T, Enger P Ø, Bjerkvig R, Sioud M, Stallcup W B
Norlux Neuro-Oncology Group, Department of Biomedicine, University of Bergen, Bergen, Norway.
Oncogene. 2008 Sep 4;27(39):5182-94. doi: 10.1038/onc.2008.157. Epub 2008 May 12.
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.
化疗耐药是许多恶性肿瘤治疗中的一个主要问题。克服这一障碍需要更好地理解导致这一现象的机制。祖细胞标志物NG2/黑色素瘤蛋白聚糖（MPG）在各种肿瘤中异常表达，但其在细胞死亡信号传导中的作用及其作为治疗靶点的潜力在很大程度上尚未得到探索。我们评估了来自15名患者的胶质母细胞瘤球体以及5种在NG2/MPG表达方面存在差异的癌细胞系中细胞毒性药物诱导的细胞死亡。这些肿瘤用阿霉素、依托泊苷、卡铂、替莫唑胺、顺铂和肿瘤坏死因子（TNF）α进行治疗。高NG2/MPG表达与由α3β1整合素/PI3K信号及其下游靶点的激活增加介导的多药耐药相关，促进细胞存活。将掺入慢病毒载体的短发夹RNA（shRNA）用于敲低NG2/MPG可减弱β1整合素信号，显示出强大的抗肿瘤作用，并在体外和体内使肿瘤细胞对细胞毒性治疗更加敏感。因此，作为抗凋亡反应的一种新型调节因子，NG2/MPG可能是几种癌症亚型中的一个有效治疗靶点。
