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- W1497357034 abstract "5314 Disruption of the function of heat shock protein 90 (HSP90) by 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is currently being tested in clinical trials. 17-AAG interferes with the binding of HSP90 to client proteins, resulting in the loss-of-function and degradation of the client protein by ubiquitination and proteasomal action. The high dose of 17-AAG required for apoptosis produces significant adverse effects. Degradation of proteins by proteasomes is inhibited by treatment with proteasomal inhibitors such as Velcade, which is under clinical trials for cancer therapy. Therefore, we determined the advantages of combined treatment with both 17-AAG and the proteasomal inhibitor, Lactacystin. Treatment of LNCaP prostate cancer cells with increasing concentrations of 17-AAG or Lactacystin, resulted in dose-dependent caspase activation and apoptosis, indicating that individually both drugs are able to induce significant apoptosis. However, combination of moderate doses of lactacystin and 17-AAG resulted in significantly greater cell death compared to individual drugs. Furthermore, treatment with 17-AAG and/or Lactacystin decreased IKK proteins, reduced phosphorylation of IκBα and decreased NFκB activity, indicating that the combination of 17-AAG and Lactacystin induced cell death by down-regulating survival pathways in addition to activating apoptotic pathways. Changes in mitogen activated protein kinase (MAPK) pathways were also examined to determine the mechanism of action of 17-AAG and Lactacystin. Lactacystin did not alter the levels of phosho-ERK1/2, while 17-AAG alone or in combination with Lactacystin significantly reduced its levels. Likewise, 17-AAG and Lactacystin alone or together reduced the expression of MKK3, which activates p38 when phosphorylated. Thus, inhibition of HSP90 interaction with members of the MAPK family altered cell cycling. In addition, in the absence of ERK1/2 signaling, Rb-e2F1 signaling may be altered, leading to the induction of p53-mediated apoptosis, as a significant increase in the expression of phospho-p53 S15 , p21 Cip1/Waf1 and p27 Kip1 proteins was noted. Alternately, the increased activation of JNK expression by Lactacystin correlated with increased apoptosis. Treatment also altered the levels of phosphorylated JNK (T183/Y185) , possibly mediated through the altered function of members of the death receptor complex. This study indicates that the therapeutic effects of 17-AAG and Lactacystin were mediated through reduced activity of the IKK-NFκB axis and/or changing the expression of proteins within the MAPK axis." @default.
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- W1497357034 date "2005-05-01" @default.
- W1497357034 modified "2023-09-28" @default.
- W1497357034 title "Therapeutic advantages of inhibition of HSP90 and proteasomal inhibition in prostate cancer cells" @default.
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