Disruption of the Bcr-Abl/Hsp90 protein complex: a possible mechanism to inhibit Bcr-Abl-positive human leukemic blasts by novobiocin.
The Bcr-Abl fusion gene encodes for the p210(Bcr-Abl) or p185(Bcr-Abl) tyrosine kinase (TK) implicated in the pathogenesis of chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia, respectively. Because Bcr-Abl TK is chaperoned by Hsp90 (90 kDa heat-shock protein), we investigated the effects of novobiocin (NB), an Hsp90 C-terminal inhibitor, on the viability of the Bcr-Abl-positive human leukemia cells HL-60/Bcr-Abl and K562, the expression of Bcr-Abl protein and the interaction between Hsp90 and Bcr-Abl TK. Present studies demonstrate that NB is a potent inhibitor of the growth of Bcr-Abl-positive human leukemia cells. NB induces cytosolic accumulation of cytochrome c and activation of caspase-9 and caspase-3, triggering apoptosis of HL-60/Bcr-Abl and K562 cells. Treatment of cell lines with NB disrupts Bcr-Abl /Hsp90 and Bcr-Abl /Hsp70 interactions, resulting in a decreased amount of intracellular Bcr-Abl protein levels. Co-treatment with the proteasome inhibitor N-acetyl leucyl-leucyl norlucinal increases NB-mediated accumulation of Bcr-Abl in the detergent-insoluble cellular fraction, which demonstrates that NB promotes proteasomal degradation of Bcr-Abl. Moreover, both imatinib-resistant K562/G01 and primary CML CD34(+) cells are sensitive to NB.
Wu
L X
LX
Deparment of Pharmacology, Institute of Clinical Pharmacology, Fujian Medical University, Fuzhou, PR China. wlx-lisa@126.com
Xu
J H
JH
Zhang
K Z
KZ
Lin
Q
Q
Huang
X W
XW
Wen
C X
CX
Chen
Y Z
YZ
D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D016227:Benzoquinones / Q000494:pharmacology; D001752:Blast Crisis / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000378:metabolism*; D018922:HL-60 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D047468:Immunoprecipitation; D020014:K562 Cells; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009675:Novobiocin / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology
D001549:Benzamides; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D010879:Piperazines; D011743:Pyrimidines; D009675:Novobiocin; D000068877:Imatinib Mesylate; D045304:Cytochromes c; D016044:Fusion Proteins, bcr-abl; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D053453:Caspase 9; D046988:Proteasome Endopeptidase Complex; C001277:geldanamycin