Targeting multiple signal transduction pathways through inhibition of Hsp90

Abstract

The multichaperone heat shock protein (Hsp) 90 complex mediates the maturation and stability of a variety of proteins, many of which are crucial in oncogenesis, including epidermal growth factor receptor (EGF-R), Her-2, AKT, Raf, p53, and cdk4. These proteins are referred to as "clients" of Hsp90. Under unstressed conditions these proteins form complexes with Hsp90 and the cochaperones to attain their active conformations or enhance stability. Inhibition of Hsp90 function disrupts the complex and leads to degradation of client proteins in a proteasome-dependent manner. This results in simultaneous interruption of many signal transduction pathways pivotal to tumor progression and survival. Based on the unique role of the Hsp90 complex, extensive effort has been made in identifying Hsp90 inhibitors. Several compounds have been shown to inhibit Hsp90 in vitro and in vivo and the most advanced, 17-allylamino-17-demethoxygeldanamycin (AAG), is in phase I/II clinical trials. Recent findings with 17-AAG indicate that tumor cells utilize Hsp90 quite differently from normal cells, explaining the selectivity of the drug and suggesting a central role of Hsp90 in malignant progression. Thus these small molecule inhibitors have proved not only to be of great value in identifying new Hsp90 client proteins and in understanding the biology of Hsp90 but are also promising therapeutics in a variety of tumors.

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

“…21 In addition to GA and 17-DMAG, HSP90 can also be inhibited by novobiocin, epigallocatechin gallate, cisplatin and others. 22,23 These alternative inhibitors differ from GA and 17-DMAG in that they exert additional effects on cellular mechanisms beyond the blockade of HSP90. 24 Recently, a synthetic HSP90 inhibitor (EC144) was found to decrease disease severity in mouse and rat models of induced arthritis.…”

Hsp90 regulates processing of NF-κB2 p100 involving protection of NF-κB-inducing kinase (NIK) from autophagy-mediated degradation

“…For example, almost all the known clients of the molecular chaperone Hsp90 (90 kDa heat-shock protein), including many important kinases and transcription factors, are found to be degraded by the proteasome when Hsp90 is inactivated by its specific inhibitor geldanamycin (GA), an anti-tumor drug [17][18][19]. On the other hand, the role of macroautophagy (simply referred to as autophagy hereafter) in the regulation of Hsp90 clients and specific signaling pathways remains largely unknown, although this mode of lysosome-dependent degradation is well-known to be the primary mechanism other than the proteasome employed for protein degradation within eukaryotes [19].…”

Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells

“…For reasons that are unclear, malignant cells seem to depend more than normal cells on Hsp90 and consequently display selective sensitivity to Hsp90 inhibition. Early clinical trials of ansamycins in solid tumours have indicated an acceptable toxicity profile, and efforts are now being focused on evaluating their effectiveness against different malignancies (Workman, 2004;Zhang and Burrows, 2004). With regard to the therapeutic potential of Hsp90 inhibition in CLL, two previous reports have shown that cultured CLL cells are sensitive to ansamycin treatment, and that this may involve depletion of the Hsp90 client proteins Akt (Jones DT et al, 2004) or ZAP-70 (Castro et al, 2005).…”