Hsp90 as a therapeutic target in endocrinology: current evidence

Abstract

Abstract:The ability of heat shock protein 90 (Hsp90) to modulate many growth and signaling pathways simultaneously makes it an attractive target in the field of cancer therapeutics and provided the initial impetus for significant efforts over the past decade to identify Hsp90 inhibitors, several of which are now showing promise in the clinic for cancer treatment. The four known human Hsp90 members are compartmentalized: Hsp90α and β in the cytoplasm, GRP94 in the endoplasmic reticulum, and TRAP1 in the mitochondrial matrix. While these isoforms share a similar N-terminal domain adenosine triphosphate-binding pocket, structural variations allow unique interactions for inhibitors targeting this binding site, providing an avenue for the development of paralog-selective drugs with different biological effects applicable therapeutically to a wide range of diseases. At the same time, the conformational flexibility of the Hsp90 molecular chaperone has unveiled multiple small-molecule target sites within all subdomains of the protein, greatly expanding opportunities for viable drug development. This review summarizes the function, expression, and clinical significance of the Hsp90 isoforms and elaborates on the inhibitors and modulators that impact Hsp90 chaperone activity. Finally, the review focuses on the therapeutic utility of a range of Hsp90-modulating agents in the treatment of specific diseases associated with the endocrine system.

Circulating Hsp90 Isoform Levels in Overweight and Obese Children and the Relation to Nonalcoholic Fatty Liver Disease: Results from a Cross-Sectional Study

“…Hepatic lipid accumulation is a chronic process that takes place over several years. It is known that Hsp90 β isoform is implied in chronic conditions and long-term adaptation responses rather than Hsp90 α isoform which usually is increased in acute stress condition [22]. It would be interesting to see if this pattern persists in adulthood (these questions would be answered by future studies on adults measuring these specific Hsp90 isoforms).…”

The Potential of Metabolomics in the Diagnosis of Thyroid Cancer

“…This protein is responsible for the folding of many proteins directly associated with malignant progression, so its inhibition could result in a combinatorial attack on numerous oncogenic pathways. Inhibition of HSP90 can therefore not only attenuate cell proliferation but also increase the efficacy of radioiodine therapy in thyroid cancer patients [29][30][31][32], making this protein a good chemotherapeutic target.…”