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Prepublished online as a Blood First Edition Paper on March 6, 2003; DOI 10.1182/blood-2002-12-3718.
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Blood, 1 July 2003, Vol. 102, No. 1, pp. 269-275
NEOPLASIA
Regulation of 17-AAG—induced apoptosis: role of Bcl-2, Bcl-xL, and Bax downstream of 17-AAG—mediated down-regulation of Akt, Raf-1, and Src kinases
Ramadevi Nimmanapalli,
Erica O'Bryan,
Deborah Kuhn,
Hirohito Yamaguchi,
Hong-Gang Wang, and
Kapil N. Bhalla
From the Department of Interdisciplinary Oncology, University of South Florida, Moffitt Cancer Center and Research Institute, Tampa, FL.
17-allylamino-demethoxy geldanamycin (17-AAG) inhibits the chaperone function of heat shock protein—90 (Hsp-90) and promotes the proteasomal degradation of its misfolded client proteins. Here, we demonstrate that treatment of the human acute myeloid leukemia HL-60 cells with 17-AAG attenuates the intracellular levels of a number of Hsp-90 client proteins, including Akt, c-Raf-1, and c-Src. Also, 17-AAG induced the mitochondrial release and cytosolic accumulation of cytochrome c (cyt c) and second mitochondria-derived activator of caspases (Smac)/DIABLO, resulting in the activation of caspase-9 and caspase-3 and apoptosis. Treatment with 17-AAG triggered the B-cell lymphoma—2 (Bcl-2)—associated X protein (Bax) conformational change associated with apoptosis, while Bax-deficient cells were resistant to 17-AAG—induced apoptosis. In addition, in HL-60/Bcl-2 and HL-60/Bcl-xL cells, which ectopically express Bcl-2 and Bcl-xL respectively, 17-AAG—induced Bax conformational change, cytosolic accumulation of cyt c and Smac/DIABLO, and apoptosis were markedly inhibited. Although the rate of 17-AAG—mediated decline in Akt, c-Raf-1, and c-Src levels was blunted, the total decline was not compromised in HL-60/Bcl-2 and HL-60/Bcl-xL cells. Cotreatment with HA14-1, a nonpeptidic ligand that can bind and inhibit the antiapoptotic activity of Bcl-2, significantly overcame the resistance to 17-AAG—induced apoptosis in HL-60/Bcl-2 cells. Together, these findings indicate that although 17-AAG treatment causes the levels of a number of survival-signaling protein kinases to decline, the downstream engagement of the mitochondrial pathway of apoptosis is regulated by the activity of the Bcl-2 family of proteins. Also, neutralizing the antiapoptotic effect of Bcl-2 would further enhance the antileukemia activity of 17-AAG. (Blood. 2003;102:269-275)
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|
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|
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|
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|
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|
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|
|
|
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|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
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|
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|
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