Heat shock protein 90 (Hsp90) is a molecular chaperone that facilitates the conformational maturation of Hsp90-dependent proteins (clients) via the Hsp90 chaperone cycle. Hsp90 functions as a homodimer and forms a large, multiprotein complex that relies upon co-chaperones, immunophilins, and partner proteins to fold nascent polypeptides, as well as the rematuration of denatured proteins. Hsp90 inhibition has emerged as a clinical strategy for the development of anticancer chemotherapeutics due to the involvement of Hsp90 clients in a variety of oncogenic signaling pathways that contribute to the six hallmarks of cancer (i. e. ErbB2, B-Raf, Akt, steroid hormone receptors, mutant p53, HIF-1, survivin, telomerase, etc.). Inhibition of this chaperone cycle results in client protein ubiquitinylation and subsequent degradation by the proteasome, resulting in tumor digression. Traditional small molecule Hsp90 inhibitors perturb the ATPase activity located at the N-terminus and include derivatives of geldanamycin, radicicol and purine. However, N-terminal inhibition of Hsp90 also leads to displacement of the Hsp90-bound transcription factor, Heat Shock Factor-1 (HSF-1). Upon N-terminal inhibition, HSF-1 translocates to the nucleus and induces transcription of the heat shock proteins, including Hsp90. This is known as the pro-survival heat shock response (HSR). Therefore, inhibitors that do not induce the HSR are sought.Alternative strategies for Hsp90 inhibition include disruption of the Hsp90 heteroprotein complex and disruption of the Hsp90 C-terminal dimerization domain. Disruption of the Hsp90 heteroprotein complex has emerged as an effective strategy to prevent client protein maturation without induction of the HSR. Disruptors of the heteroprotein complex inhibit cancer cell proliferation at concentrations similar to N-terminal inhibitors and results in client degradation. Herein, I will discuss cucurbitacins D and isoD as disruptors of client maturation and the mechanism by which these cucurbitacins induce the degradation of client proteins without induction of the HSR.

Cucurbitacins as novel inhibitors of Hsp90 chaperone function

248th National Meeting (2014)

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