期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 295, 期 22, 页码 7774-7788出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA120.013778
关键词
glioblastoma; cancer stem cells; chemoresistance; anticancer drug; cell cycle; apoptosis; tumor marker; temozolomide; ATP-binding cassette subfamily B member 5 (ABCB5); glioblastoma multiforme; CD133
资金
- National Institutes of Health [T32 EB016652-05]
- Vetarans Affairs BLRD Grant [1I01BX000516]
- Vetarans Affairs RRDGrant [1I01RX000989]
- Merit Review Awards
- Department of Defense translational team science award
- NCI, National Institutes of Health [R01CA113796, R01CA158467, R01CA138231]
- NEI, National Institutes of Health [1RO1EY025794, R24EY028767]
Glioblastoma multiforme (GBM) is a malignant brain tumor with a poor prognosis resulting from tumor resistance to anticancer therapy and a high recurrence rate. Compelling evidence suggests that this is driven by subpopulations of cancer stem cells (CSCs) with tumor-initiating potential. ABC subfamily B member 5 (ABCB5) has been identified as a molecular marker for distinct subsets of chemoresistant tumor-initiating cell populations in diverse human malignancies. In the current study, we examined the potential role of ABCB5 in growth and chemoresistance of GBM. We found that ABCB5 is expressed in primary GBM tumors, in which its expression was significantly correlated with the CSC marker protein CD133 and with overall poor survival. Moreover, ABCB5 was also expressed by CD133-positive CSCs in the established human U-87 MG, LN-18, and LN-229 GBM cell lines. Antibody- or shRNA-mediated functional ABCB5 blockade inhibited proliferation and survival of GBM cells and sensitized them to temozolomide (TMZ)-induced apoptosis in vitro. Likewise, in in vivo human GBM xenograft experiments with immunodeficient mice, mAb treatment inhibited growth of mutant TP53, WT PTEN LN-229 tumors, and sensitized LN-229 tumors to TMZ therapy. Mechanistically, we demonstrate that ABCB5 blockade inhibits TMZ-induced G(2)/M arrest and augments TMZ-mediated cell death. Our results identify ABCB5 as a GBM chemoresistance marker and point to the potential utility of targeting ABCB5 to improve current GBM therapies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据