Proteomic scale effect of HSP90 inhibition with 17-AAG and radicicol

Heat Shock Protein 90 is a molecular chaperone with a function of folding the proteins involved in cell signaling, such as transcription factors and protein kinases. Under stressful conditions, HSP90 stabilizes its client proteins and provides protection to the cell against cellular stressors such as in cancer cells. Through mutations, cancer cells become dependent on oncogenic pathways. Then the most malignant tumor cells are selected for cloning. As this malignant process proceeds, there is a need for the up-regulation of HSP90. The dependency of the cancer cells on HSP90 increases to a great extent as HSP90 protects the overexpressed and unstable oncogenic proteins. Therefore, it makes sense to say that if we inhibit HSP90 it would be beneficial for all types of cancer. The promising anti-tumor activity of 17-allylamino-17demethoxygeldanamycin (17AAG) and Radicicol results from the inhibition of HSP90. Proteomic analysis was done to study the effect of HSP90 inhibitors after 24 hours of drug treatment. Lung epithelial cancer cells were given a treatment of 60nM of 17AAG and 600nM of Radicicol. Mass Spectrometry (LC-MS/MS) and Western Blotting were used to analyze the drug treated and untreated samples. The drugs bind at the ATP pocket of HSP90 and disrupt the HSP90 complex that stabilizes the client proteins. An increase in the expression of HSP90 and HSP70 is observed. This might mean that the complex that assists in folding of the client proteins is disrupted which can be beneficial, as the cancer cells would be deprived of the oncogenic proteins that they rely on. Furthermore, the results from drug treated A549 cells were compared to Mesenchymal Stem Cells (MSC's). This can help in studying the effect of drugs on a wider variety of cells. MSC's are undifferentiated cells; which can differentiate into various cell types, example adipocytes, chondrocytes and cardiomyocytes. Giving the drug treatment to MSC's would help us in understanding the effect of the drugs on the cells and whether the cells were harmed or not. This information can prove to be beneficial before testing the drugs in people. Hence treating MSC with 17-AAG and Radicicol would help in testing the safety and quality of the drugs.