Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells.
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 (TNF-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/hsp70) 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 leukemia-blast crisis and acute myeloid leukemia cells.
Mesh Terms:
Apoptosis, Cell Line, Tumor, DNA Primers, DNA-Binding Proteins, Fusion Proteins, bcr-abl, HL-60 Cells, HSP70 Heat-Shock Proteins, Humans, Jurkat Cells, Leukemia, Myeloid, Acute, Milk Proteins, Proto-Oncogene Proteins c-bcl-2, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, STAT5 Transcription Factor, Trans-Activators, bcl-2-Associated X Protein, bcl-X Protein
Apoptosis, Cell Line, Tumor, DNA Primers, DNA-Binding Proteins, Fusion Proteins, bcr-abl, HL-60 Cells, HSP70 Heat-Shock Proteins, Humans, Jurkat Cells, Leukemia, Myeloid, Acute, Milk Proteins, Proto-Oncogene Proteins c-bcl-2, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, STAT5 Transcription Factor, Trans-Activators, bcl-2-Associated X Protein, bcl-X Protein
Blood
Date: Feb. 01, 2005
PubMed ID: 15388581
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