Therapeutic and diagnostic implications of Hsp90 activation

Adeela Kamal, Marcus F Boehm, Francis J Burrows, Adeela Kamal, Marcus F Boehm, Francis J Burrows

Abstract

The molecular chaperone heat-shock protein 90 (Hsp90) is involved in the stabilization and conformational maturation of many signaling proteins that are deregulated in cancers. Hsp90 inhibition results in the proteasomal degradation of these client proteins and leads to potent antitumor activity. The Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG) is presently in clinical trials. Recent work has identified the role of Hsp90 in multiple signal transduction pathways and revealed that the molecular mechanism of tumor selectivity by Hsp90 inhibitors is the result of an activated, high-affinity conformation of Hsp90 in tumors. This review discusses these recent advances in the understanding of tumor Hsp90 for the treatment and diagnosis of cancer. In addition, the role of Hsp90 in non-oncological diseases will also be discussed.

Figures

Figure 1
Figure 1
The Hsp90 chaperoning cycle. The Hsp90 chaperoning cycle is a dynamic process in which client proteins bind to Hsp90 in an intermediate complex containing the co-chaperones Hsp70, Hsp40, Hip and Hop. Upon ATP binding and hydrolysis, Hsp90 forms a mature complex, containing p23, p50/cdc37 and immunophilins (IP), which catalyzes the conformational maturation of Hsp90 client proteins. Hsp90-inhibitor drugs, such as geldanamycin (GM), bind to the N-terminal ATP-binding pocket of Hsp90 and inhibit ATP binding and hydrolysis, thereby locking Hsp90 in the intermediate complex. The client protein is subsequently ubiquitinated (possibly by a E3 ubiquitin ligase) and targeted to the proteasome for degradation.
Figure 2
Figure 2
Hsp90 client proteins regulate multiple signal transduction pathways that are deregulated in cancers. Hsp90 client proteins (shown in bold) include key components of the mitogenic signaling pathway that drives cell-cycle progression, as well as survival signal transduction pathways that inhibit apoptosis. Hsp90 client proteins include growth factor receptors (HER-2, IGF-1R, EGF-R and PDGF-R), signaling kinases (Akt and Raf-1), cell-cycle regulators (cdk4) and nuclear steroid receptors (AR and ER). Abbreviations: AR, androgen receptor; EGF-R, epidermal growth factor receptor; ER, estrogen receptor; IGF-1R, insulin-like growth factor-1 receptor; PDGF-R, platelet-derived growth factor receptor.
Figure 3
Figure 3
Model for tumor selectivity of Hsp90 inhibitors and Hsp90-dependent malignant progression. Hsp90 in normal cells exists in an uncomplexed form that has low-affinity for Hsp90 inhibitor drugs, which accumulate poorly in normal tissues, and normal cells exhibit poor drug sensitivity. By contrast, the Hsp90 in cancer cells is involved in the active chaperoning of overexpressed oncoproteins and exists in a complexed form with co-chaperone proteins (p23 and Hop are not in the same complex). Complexed Hsp90 in cancer cells exhibits high-affinity binding to Hsp90 inhibitor drugs, which accumulate in tumor tissues, and tumor cells exhibit good drug sensitivity. This model predicts that the accumulation of mutant proteins in advanced cancer would further increase Hsp90 usage and make tumor cells more Hsp90 dependent. Furthermore, this model suggests that the high-affinity change of Hsp90 can be driven by the overexpression of oncoproteins, as well as by stressful conditions in normal cells (e.g. heat).
Figure 4
Figure 4
Hsp90 inhibitors. Chemical structures of geldanamycin, radicicol, ATP and PU3.

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