[Hsp90 inhibitors versus CLL via degradation of ZAP-70]
>>Blood. 2005 Jun 21; [Epub ahead of print]
ZAP-70 is a novel conditional heat shock protein 90 (Hsp90)-client protein: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis and impaired signaling in chronic lymphocytic leukemia.
Castro JE, Prada CE, Loria O, Kamal A, Chen L, Burrows FJ, Kipps TJ.
Moores UCSD Cancer Center, University of California, San Diego, CA, USA; Chronic Lymphocytic Leukemia Research Consortium (CRC), San Diego, CA, USA.
ZAP-70 is expressed in patients with aggressive chronic lymphocytic leukemia (CLL). We found that ZAP-70(+) CLL cells, expressed activated heat-shock protein 90 (Hsp90) with high binding-affinity for Hsp90-inhibitors, such as 17-allyl-amino-demethoxy-geldanamycin (17-AAG), whereas normal lymphocytes or ZAP-70-negative CLL cells expressed non-activated Hsp90. Activated Hsp90 bound and stabilized ZAP-70, which behaved like an Hsp90 client protein only in CLL cells. Treatment with Hsp90 inhibitors such as 17-AAG and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), induced ZAP-70 degradation and apoptosis in CLL cells but not in T cells, and also impaired B-cell receptor signaling in leukemia cells. Transduction of ZAP-70-negative CLL cells with an adenovirus encoding ZAP-70 activated Hsp90 and specifically rendered the leukemia cells sensitive to 17-AAG. These data indicate that Hsp90 is necessary for ZAP-70 expression and activity; that ZAP-70 is unique among Hsp90 clients, in that its chaperone-dependency is conditional upon the cell type in which it is expressed, and also that ZAP-70 is required for cell survival and signaling in CLL. Additionally, ZAP-70 expression in CLL cells confers markedly heightened sensitivity to 17-AAG or 17-DMAG, suggesting that these or other Hsp90 inhibitors could be valuable therapeutically in patients with aggressive CLL.<<
Cheers, Tuck |
