Abstract
HSP90 operates with cochaperones to enable the correct folding, stabilisation and functioning of multiple oncogenic protein kinases, hormone receptors, and transcription factors, thus making HSP90 an exciting drug target. HSP90 inhibition results in proteasomal degradation of client proteins via ubiquitination by E3 ligases such as CHIP. This cochaperone functions with HSP90 as a molecular switch, sorting misfolded proteins between the degradation and chaperone pathways during a stressed state. We hypothesised that CHIP modulation in human cancer cells may affect their sensitivity to HSP90 inhibition.
A range of levels of constitutive CHIP expression were seen across a panel of human cancer cell lines, as measured by western blotting. Additionally, CHIP levels were unaffected by treatment with HSP90 inhibitors. Interestingly, both overexpression and RNAi knockdown of CHIP caused a significant increase in cellular sensitivity to 17‐AAG. Depletion of client proteins were still observed in both overexpression and knockdown cells following treatment with 17‐AAG. However, differences in the rate of depletion of some, but not all HSP90 clients, were identified.
The results demonstrate that modulating CHIP levels sensitizes cells to 17‐ AAG but at the same time that E3‐ligase redundancy may exist as a mechanism to ensure client depletion during HSP90 inhibition.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B83.
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