Relevance of the ATPase activity of Hsp90 on its biological action in prostate cancer cells

FEDERICCI F.; GALIGNIANA M.D.; GUPTA D; MAZAIRA G.I.; CIUCCI S.; ERLEJMAN A.G.

San Diego

Congreso; Ninth International Congress On Stress Responses In Biology & Medicine; 2019

Cell Stress Society International

Hsp90 inhibitors are to date the only known chemotherapeutic agent that shows strong effects in all hallmarks of cancer. Therefore, it is considered a promising molecular target for cancer treatment. Hsp90 stabilizes the active conformation of cognate client proteins already exhibiting a stable tertiary structure, among them, steroid receptors and several oncoproteins. Various Hsp90 inhibitors are being tested in clinical and preclinical studies with different results, and new ones are being synthesized to optimize their properties. Our aim was to analyze the biological actions of synthetic compounds predesigned by computational modeling according to the potential inhibitory effect on the intrinsic ATPase activity, which is regarded as essential for Hsp90 biological function. Some derivatives were Schiff bases derived from 2,4-dihydroxybenzaldehyde or 5-chloro-2,4-dihydroxybenzaldehyde, and others were resorcinol derivatives. Previous studies suggested that these base structures could improve the interaction with the target with minimal toxic side-effects. Studies performed with PC3 prostate cancer cells showed that, in contrast to geldanamycin (a standard Hsp90 inhibitor), the retrotransport of primarily cytoplasmic steroid receptors was unaffected by any synthetic drug. Nevertheless, four compounds (named S3, S8, S31 and S42) decreased cell viability showing percentages comparable to those of geldanamycin (48.56 ± 4.44 %) after 48 h of treatment. Also, these drugs affected other Hsp90-dependent processes important for tumor progression such as cell migration and metalloprotease activity. In contrast to what it has always been assumed in the literature, a direct relationship between biological action and ATPase activity was evidenced. In summary, our study characterizes new Hsp90 inhibitory drugs that may have potential pharmacologic application, and demonstrates that the ATPase enzymatic activity of Hsp90 is not correlated with the biological action of the chaperone.