Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells.

Abstract

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.

• Authors: Fei Guo, Celia Sigua, Purva Bali, Prince George, Warren Fiskus, Anna Scuto, Srinivas Annavarapu, Abdelmoughite Mouttaki, Gautam Sondarva, Sheng Wei, Jie Wu, Julie Djeu, Kapil Bhalla
• Journal: Blood (Blood) Vol. 105 Issue 3 Pg. 1246-55 (Feb 01 2005) ISSN: 0006-4971 [Print] United States
• PMID: 15388581 (Publication Type: Journal Article)

Chemical References

• BAX protein, human
• BCL2L1 protein, human
• DNA Primers
• DNA-Binding Proteins
• HSP70 Heat-Shock Proteins
• Milk Proteins
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• STAT5 Transcription Factor
• Trans-Activators
• bcl-2-Associated X Protein
• bcl-X Protein
• Fusion Proteins, bcr-abl

Topics

• Apoptosis (physiology)
• Cell Line, Tumor
• DNA Primers
• DNA-Binding Proteins (genetics, metabolism)
• Fusion Proteins, bcr-abl (physiology)
• HL-60 Cells
• HSP70 Heat-Shock Proteins (genetics, physiology)
• Humans
• Jurkat Cells
• Leukemia, Myeloid, Acute
• Milk Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT5 Transcription Factor
• Trans-Activators (genetics, metabolism)
• bcl-2-Associated X Protein
• bcl-X Protein