BECN1 and BIM interactions with MCL-1 determine fludarabine resistance in leukemic B cells

被引:33
|
作者
Sharma, A. [1 ,2 ]
Singh, K. [1 ]
Mazumder, S. [1 ]
Hill, B. T. [3 ]
Kalaycio, M. [3 ]
Almasan, A. [1 ]
机构
[1] Cleveland Clin, Lerner Res Inst, Dept Canc Biol, Cleveland, OH 44195 USA
[2] Cleveland State Univ, Cleveland, OH 44115 USA
[3] Cleveland Clin, Taussig Canc Inst, Dept Hematol Oncol & Blood Disorders, Cleveland, OH 44106 USA
来源
CELL DEATH & DISEASE | 2013年 / 4卷
基金
美国国家卫生研究院;
关键词
autophagy; MCL-1; BECN1; BIM; fludarabine resistance; CHRONIC LYMPHOCYTIC-LEUKEMIA; CYTOCHROME-C RELEASE; CASPASE ACTIVATION; UP-REGULATION; AUTOPHAGY; BCL-2; EXPRESSION; PHOSPHORYLATION; APOPTOSIS; DEATH;
D O I
10.1038/cddis.2013.155
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The purine analog fludarabine (Fd) is an essential therapeutic for chronic lymphocytic leukemia (CLL). Innate or acquired resistance to Fd is a significant clinical problem and is largely mediated by increased expression of BCL-2 family members. The antiapoptotic BCL-2 family proteins inhibit both apoptosis and autophagy, therefore, downregulation of antiapoptotic BCL-2 family proteins and enhanced autophagy must coexist in cells dying in response to an apoptosis inducing therapeutic. However, in the drug-resistant cells that have an increased dependence on antiapoptotic proteins, whether autophagy is also inhibited remains unclear. Here, we examined the role of the BCL-2 family in regulating cell death and autophagy in leukemic cell lines and their derivative isogenic Fd-resistant (FdR) cells. MCL-1 degradation following Fd treatment freed the proapoptotic effectors BIM and BECN1, thus leading to cell death-associated autophagy in Fd-sensitive cells. However, in FdR cells, low BIM expression and BECN1 sequestration by MCL-1 prevented cell death. Consistently, in sensitive cells inhibition of apoptosis using siBIM and of both the early-phase autophagy nucleation steps by siBECN1, shATG7 or 3-methyladenine and the late-phase autophagy by shLAMP2, significantly reduced Fd-induced cell death. Paradoxically, FdR cells were addicted to basal autophagy, which was dependent on AMP-activated protein kinase (AMPK) but not BECN1. Moreover, in FdR cells, inhibition of autophagy by shLAMP2, but not siBECN1, enhanced cell death. The BH3-mimetic obatoclax released BIM and BECN1 from MCL-1 in Fd-sensitive and BECN1 from MCL-1 in FdR cells, and was effective at killing both Fd-sensitive and - resistant leukemic cells, including primary CLL cells. Therefore, a differential regulation of autophagy through BECN1 and AMPK signaling in Fd-sensitive and - resistant cells determines the different possible outcomes of autophagy inhibition. These findings suggest effective means to overcome Fd resistance by induction of BIM-dependent apoptosis and activation of BECN1-dependent autophagy.
引用
收藏
页码:e628 / e628
页数:10
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