Sensitization of imatinib-resistant CML cells to TRAIL-induced apoptosis is mediated through down-regulation of Bcr-Abl as well as c-FLIP.

Abstract

Resistance to imatinib is commonly associated with reactivation of Bcr-Abl signalling. However, Bcr-Abl-independent signalling pathways may be activated and contributed to imatinib resistance in some CML (chronic myelogenous leukaemia) patients. We had isolated three imatinib-resistant K562/R1, R2 and R3 variants with gradual loss of Bcr-Abl from K562 cells to develop effective therapeutic strategies for imatinib-resistant CML. Interestingly, we found that these cells became highly sensitive to TRAIL (tumour necrosis factor-related apoptosis-inducing factor) in comparison with K562 cells showing high resistance to TRAIL. Treatment of K562/R3 cells with TRAIL resulted in activation of TRAIL receptor pathway by including caspase 8 activation, Bid cleavage, cytochrome c release and caspase 3 activation. These results were accompanied by down-regulation of c-FLIP {cellular FLICE [FADD (Fas-associated death domain)-like interleukin 1beta-converting enzyme]-inhibitory protein} in imatinib-resistant K562 variants compared with K562 cells. Overexpression of c-FLIP in K562/R3 cells acquired TRAIL resistance and conversely, c-FLIP-silenced K562 cells became sensitive to TRAIL. Moreover, Bcr-Abl-silenced K562 cells showed down-regulation of c-FLIP and the subsequent overcome of TRAIL resistance. Taken together, our results demonstrated for the first time that the loss of Bcr-Abl in imatinib-resistant cells led to the down-regulation of c-FLIP and subsequent increase of TRAIL sensitivity, suggesting that TRAIL could be an effective strategy for the treatment of imatinib-resistant CML with loss of Bcr-Abl.

• Authors: Soo-Jung Park, Mi-Ju Kim, Hak-Bong Kim, Chi-Dug Kang, Sun-Hee Kim
• Journal: The Biochemical journal (Biochem J) Vol. 420 Issue 1 Pg. 73-81 (Apr 28 2009) ISSN: 1470-8728 [Electronic] England
• PMID: 19203346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• Piperazines
• Pyrimidines
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Imatinib Mesylate
• Fusion Proteins, bcr-abl

Topics

• Apoptosis
• Benzamides
• CASP8 and FADD-Like Apoptosis Regulating Protein (genetics)
• Down-Regulation
• Drug Resistance, Neoplasm
• Fusion Proteins, bcr-abl (genetics)
• Gene Silencing
• Humans
• Imatinib Mesylate
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (pathology)
• Piperazines (pharmacology)
• Pyrimidines (pharmacology)
• TNF-Related Apoptosis-Inducing Ligand (physiology)