Regulation of AR and GR biological response by TPR-domain proteins

MAZAIRA, G; CIUCCI, S; ROZOWYKWIAT, E; MARTINEZ DORR, A; ERLEJAMN, A; GALIGNIANA, M

San Diego, California

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

Cell Stress Society International

The best characterized proteins showing TPR (tetratricopeptide repeats) domains are those belonging to steroid receptor-Hsp90 heterocomplex. The TPR-domain immunophilins FKBP51 and FKBP52 were first characterized due to their ability to regulate both the subcellular localization of GR and its transcriptional activity. In this study, our aim was to analyze the effects of other TPR proteins such as PP5, SGT1α and 14-3-3σ on GR and AR regulation in a prostate cancer cell line (PC3 cells). The overexpression of PP5 favored GR nuclear retention, whereas 14-3-3σ overexpression showed the opposite action by delaying GR import and accelerating its nuclear export. While SGT1α did not affect the subcellular distribution of both receptors, their transcriptional activities were abrogated. Interestingly, PP5 and 14-3-3σ showed a biphasic response on transcriptional activity, that is, stimulation by a slight increase in their expression, but inhibition with higher levels. All three TPR proteins did not affect AR nuclear import rate. Nonetheless, while PP5 was able to stimulate AR activity, both 14-3-3σ and SGT1α inhibited transcription. These observations suggest that the expression balance of these TPR proteins could affect the balance of the antagonistic biological activity of AR and GR in the development and progression of prostate cancer cells. In view of the current lack of specific drugs for each TPR protein, and because TPR proteín?Hsp90-complexes form a structural and functional unit, we used novel synthetic inhibitors of Hsp90 to target PC3 prostate cancer cells. We tested derivatives of 2,4-dihydroxybenzaldehyde, 5-chloro-2,4-dihydroxybenzaldehyde, or resorcinol designed by molecular docking as potential inhibitors of the ATPase activity of Hsp90, which is classically considered essential for the biological function of chaperone. All the assayed novel compounds decreased cell viability. However, neither the steroid receptor import nor their transcriptional activity were affected in direct correlation with their action on the Hsp90 ATPase activity. This work describes for the first time the effects of these three TPR factors on the biological response of a prostate cancer cell line and the possible use of these heterocomplex as novel therapeutic targets.