Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells
Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells
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DOI：
10.1182/blood-2004-05-2041
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发表时间：
2005-02-01
期刊：
影响因子：
20.3
通讯作者：
Bhalla, K
中科院分区：
文献类型：
--
作者：
Guo, F;Sigua, C;Bhalla, K
表达bcr - abl的原代或培养白血病细胞显示出高水平的抗凋亡热休克蛋白（hsp） 70，并对阿糖胞苷（Ara-C）、乙酰基苷或Apo-2L/TRAIL （tnf相关的凋亡诱导配体）诱导的凋亡具有抗性。相反，hsp70 cDNA的反向稳定表达不仅降低了hsp70，还降低了信号转导和转录激活因子5 （STAT5）和Bcl-X-L的水平。阿糖胞苷、依托泊苷或Apo-2L/TRAIL诱导的细胞凋亡增加。hsp70在HL-60细胞中的异位表达（HL-60/ hsp70）抑制了Ara-C和依托oposide诱导的Bax构象改变和线粒体易位；降低了胞浆中细胞色素c、Smac和Omi/HtrA2的积累；抑制caspase-9和caspase-3的加工和活性。Hsp70与死亡受体4和5 （DR4和DR5）结合，抑制Apo-2L trail诱导的死亡诱导信号复合体（DISC）的组装和活性。HL-60/hsp70细胞显示STAT5水平和DNA结合活性升高，这与Pim-2和Bcl-X-L的高水平和对凋亡的抗性有关。显性阴性（DN） STAT5的表达使HL-60/ hsp70细胞对阿糖胞苷、依托opo苷和Apo-2L/ trail诱导的凋亡重新敏感。总之，这些发现表明，hsp70抑制线粒体上游和下游的细胞凋亡，是逆转慢性髓系白血病危像和急性髓系白血病细胞耐药的有希望的治疗靶点。(C) 2005年由美国血液病学会出版。
Bcr-Abl-expressing primary or cultured leukemia cells display high levels of the antiapoptotic heat shock protein (hsp) 70 and are resistant to cytarabine (Ara-C), etoposide, or Apo-2L/TRAIL (TNIF-related apoptosis-inducing ligand)-induced apoptosis. Conversely, a stable expression of the cDNA of hsp70 in the reverse orientation attenuated not only hsp70 but also signal transducers and activators of transcription 5 (STAT5) and Bcl-X-L levels. This increased apoptosis induced by cytarabine, etoposide, or Apo-2L/TRAIL. Ectopic expression of hsp70 in HL-60 cells (HL-60/hsp7O) inhibited Ara-C and etoposide-induced Bax conformation change and translocation to the mitochondria; attenuated the accumulation of cytochrome c, Smac, and Omi/HtrA2 in the cytosol; and inhibited the processing and activity of caspase-9 and caspase-3. Hsp70 was bound to death receptors 4 and 5 (DR4 and DR5) and inhibited Apo-2L TRAIL-induced assembly and activity of the death-inducing signaling complex (DISC). HL-60/hsp70 cells exhibited increased levels and DNA binding activity of STAT5, which was associated with high levels of Pim-2 and Bcl-X-L and resistance to apoptosis. Expression of the dominant negative (DN) STAT5 resensitized HL-60/ hsp70 cells to cytarabine, etoposide, and Apo-2L/TRAIL-induced apoptosis. Collectively, these findings suggest that hsp70 inhibits apoptosis upstream and downstream of the mitochondria and is a promising therapeutic target for reversing drug-resistance in chronic myeloid leukemiablast crisis and acute myeloid leukemia cells. (C) 2005 by The American Society of Hematology.