Inhibition of Heat Shock Proteins Affect NFkB Function Through IKK Proteins

摘要

Heat shock proteins (HSP) are molecular chaperones whose increased expression has been correlated with cancer, resistance to chemo- and radio-therapy. Inhibition of HSP90 function by treatment with geldanamycin (GA) or 17AAG is being tested in clinical trials for cancer therapy. However, it was shown that at the doses required to induce apoptosis, these drugs demonstrate adverse effects. Our working plan is to identify a sub-lethal dose of GA-17AAG to disrupt the function of the HSP client proteins and to induce apoptosis using a known apoptotic agent, such as TRAIL. We hypothesized that lowering the activity of survival proteins will provide apoptotic advantage. We have demonstrated that a combination of sublethal dose of GA/17-AAG and TRAIL induced significant apoptosis in prostate cancer cells. Furthermore, we have observed that GA and TRAIL inhibited the function of IKK proteins, leading to inhibition of the activity of NFkappaB.