Chen Yongqiang, Henson Elizabeth S, Xiao Wenyan, Shome Epsita, Azad Meghan B, Burton Teralee R, Queau Michelle, Sathya Akshay, Eisenstat David D, Gibson Spencer B
a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Canada.
b Department of Biochemistry and Medical Genetics , University of Manitoba , Winnipeg , Canada.
Cancer Biol Ther. 2016 Jun 2;17(6):604-13. doi: 10.1080/15384047.2015.1095399. Epub 2015 Oct 15.
Mcl-1 is an anti-apoptotic Bcl-2 family member that is often over-expressed in the malignant brain tumor glioblastoma (GBM). It has been previously shown that epidermal growth factor receptors up-regulate Mcl-1 contributing to a cell survival response. Hypoxia is a poor prognostic marker in glioblastoma despite the fact that hypoxic regions have areas of necrosis. Hypoxic regions of GBM also highly express the pro-cell death Bcl-2 family member BNIP3, yet when BNIP3 is overexpressed in glioma cells, it induces cell death. The reasons for this discrepancy are unclear. Herein we have found that Mcl-1 expression is reduced under hypoxia due to degradation by the E3 ligase FBW7 leading to increased hypoxia induced cell death. This cell death is reduced by EGFR activation leading to increased Mcl-1 expression under hypoxia. Conversely, BNIP3 is over-expressed in hypoxia at times when Mcl-1 expression is decreased. Knocking down BNIP3 expression reduces hypoxia cell death and Mcl-1 expression effectively blocks BNIP3 induced cell death. Of significance, BNIP3 and Mcl-1 are co-localized under hypoxia in glioma cells. These results suggest that Mcl-1 can block the ability of BNIP3 to induce cell death under hypoxia in GBM tumors.
髓细胞白血病-1（Mcl-1）是一种抗凋亡的Bcl-2家族成员，在恶性脑肿瘤胶质母细胞瘤（GBM）中常过度表达。先前研究表明，表皮生长因子受体上调Mcl-1，从而促进细胞存活反应。尽管胶质母细胞瘤的缺氧区域存在坏死区域，但缺氧仍是其不良预后指标。GBM的缺氧区域也高表达促细胞死亡的Bcl-2家族成员BNIP3，然而，当BNIP3在胶质瘤细胞中过度表达时，却会诱导细胞死亡。这种差异的原因尚不清楚。在此我们发现，在缺氧条件下，E3连接酶FBW7介导的降解导致Mcl-1表达降低，进而增加缺氧诱导的细胞死亡。表皮生长因子受体（EGFR）激活可增加缺氧条件下的Mcl-1表达，从而减少这种细胞死亡。相反，在Mcl-1表达降低时，BNIP3在缺氧状态下过度表达。敲低BNIP3表达可减少缺氧诱导的细胞死亡，而Mcl-1表达有效阻断BNIP3诱导的细胞死亡。重要的是，在胶质瘤细胞缺氧条件下，BNIP3和Mcl-1共定位。这些结果表明，在GBM肿瘤缺氧条件下，Mcl-1可阻断BNIP3诱导细胞死亡的能力。
