Hsp70 and Hsp90, abundantly and preferentially expressed in human tumors, are proteins necessary to maintain the dysregulated function of cancer cells. Both chaperones, but especially Hsp70, inhibit key effectors of the apoptotic machinery including the apoptosome, the caspase activation complex, and apoptosis inducing factor. They also play a role in the proteasome-mediated degradation of apoptosis-regulatory proteins. Activation of signaling pathways mediated by Hsp90-client proteins such as steroid receptors, Raf1 and Akt is necessary for the growth and survival of many tumors. Besides their anti-apoptotic and survival promoting roles, the overexpression of Hsp70 and Hsp90 in several cell types is documented to increase transformation. These chaperones were found to be required for the correct conformation, function and stability of mostly kinases, hormone receptors and transcription factors that are directly involved in driving multistep malignancy and of mutated oncogenic proteins required for the transformed phenotype. Besides their vital role in maintaining cancer cell physiology, HSP induction, particularly of Hsp70, has been proposed to lead to anti-cancer therapy resistance. The ability of Hsp70 to prevent apoptosis induced by several anticancer drugs and other therapeutic interventions explains how this protein could limit the efficacy of cancer therapy. Indirect experimental evidence and clinico-pathological studies indicate that Hsp70 is the major stress inducible, cancer-associated, anti-apoptotic protein. These collective observations suggest Hsp70 and Hsp90 as targets in cancer therapy. In this regard, our group is interested in developing agents that interfere either with the activity or expression of these chaperones.
