Abstract 2074: Hsp27 inhibition activates the unfold protein response and autophagy pathway through inhibition of proteasome activity in prostate cancer
Notice bibliographique
Résumé
Abstract Introduction and objectives: Hsp27 is a stress-activated, multifunctional chaperone that inhibits treatment-induced apoptosis and is highly expressed in castrate-resistant prostate cancer. Hsp27 is induced by accumulation of unfolded protein aggregates following various stress conditions, and promotes folding of proteins to their native state or degrading misfolded proteins via the ubiquitin-proteasome pathway (UPP). The specific signaling that occurs between the endoplasmic reticulum (ER) and the nucleus in response to ER stress is known as the unfolded protein response (UPR). During the UPR, accumulated unfolded protein is either correctly refolded or degraded by the UPP, but when unfolded protein levels exceed a threshold, damaged cells are committed to cell death. Recently, there has been an increased general interest in understanding the interactions of ER stress, proteasome and autophagy in protein clearance. However, it is still unclear whether ER stress-mediated autophagy is involved in cell survival or cell death. We hypothesize that inhibition of Hsp27 will enhance ER stress and treatment-induced cancer cell death by increasing unfolded protein burden. We set out to characterize the role of Hsp27 in ER stress and UPR in prostate cancer. Methods: Effects of Hsp27 silencing using siRNA or antisense inhibitor (OGX-427) or proteasome inhibition (MG132) on PC3 cell apoptosis and putative targets of UPR were compared. Proteasome activity was measured using fluorescent substrate of proteasome in Hsp27 inhibited or overexpressed PC3 cells. We also evaluated autophagy activity after Hsp27 knockdown and cell viability after combination treatment with Hsp27 knockdown +/- inhibition of autophagy by 3-methyladenine (3-MA). Results: Hsp27 expression and other components of the UPR were activated in PC-3 cells after treatment with MG132 with accumulation of ubiquitinated proteins. Hsp27 knockdown was associated with decreased proteasome activity, increased ubiquitinated protein levels, and activation of UPR, similar to that seen with MG132. In contrast, Hsp27 overexpressing PC3 cells exhibited increased proteasome activity and resistance to MG-132 induced cell death and UPR activation compared to control cells. The inhibition of Hsp27 also led to increased autophagy activity. Furthermore, the combination treatment with Hsp27 silencing and 3MA significantly reduced PC3 cell viability and induced apoptosis. Conclusions: These results suggest that Hsp27 enhances the catalytic activity of the proteasome and increases the degradation rate of ubiquitinated proteins. Moreover, the inhibition of both Hsp27 and autophagy enhances prostate cancer cell death and represents a useful therapeutic strategy to target for anti-cancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2074. doi:10.1158/1538-7445.AM2011-2074
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».