Abstract 3386: Post-translational mechanisms related to PAR-4 regulation in endometrial cancer
Notice bibliographique
Résumé
Abstract Prostate Apoptosis Response-4 (PAR-4) is a tumor suppressor protein whose expression level in cancer is frequently decreased; however it is neither mutated nor suppressed. A unique feature of PAR-4 is that it can induce apoptosis selectively in cancer cells without destroying normal cells, giving it an interest in anti-cancer targeted therapy. PAR-4 is not only regulated at the expression level, but also post-translationally by phosphorylation and protein cleavage. Most recently, the caspase-3 cleaved form of PAR-4 has been demonstrated by our laboratory and this fragment might be responsible for PAR-4 apoptosis mechanism. In the present study, we have investigated the mechanisms regulating PAR-4 and its cleaved form in endometrial cancer cell lines. Using endometrial cisplatin-sensitive cell line (Ishikawa) and endometrial cisplatin-resistant cell lines (HEC-1A), we compared expression level of PAR-4 and its cleaved form (cl.PAR-4) after treatment with cisplatin. PAR-4 level was decreased more in sensitive cancer cells and cl.PAR-4 was then increased indicating a possible link with chemoresistance. To further investigate mechanisms by which cl.PAR-4 is linked to apoptosis, we produced stable Ishikawa and HEC-1A cells clones expressing cl.PAR-4-MYC using lentiviral particles. Our first observations were that, upon cisplatin treatment, cl.PAR-4-MYC protein level was increased while cDNA level was stable indicating post-translational mechanisms regulating cl.PAR-4. Using proteasome inhibitors, MG-132 and lactacystin, cl.PAR-4-MYC expression level increased indicating a link between cl.PAR-4 and the proteasome. We also investigated the role of AKT in relation with cl.PAR-4 using the PI3K inhibitor Wortmannin. Results indicated that pAKT negatively regulate cl.PAR-4-MYC dose-dependently. We also found out that phospho-PAR-4 Thr163 is highly expressed in mutated-PTEN endometrial cancer cell line Ishikawa and RL95-2 which are expressing high level of phospho-AKT. We investigated the localization of PAR-4 and cl.PAR-4 using cytoplasmic/nuclear fractionation and the results indicates that cl.PAR-4-MYC and endogenous PAR-4 are localized in both nucleus and cytoplasm while endogenous cl.PAR-4 is mainly cytosolic. This localization of cl.PAR-4 may have a role in its ability to induce apoptosis like full length PAR-4. Finally, bioinformatic analyses have been done to suggest potential ubiquitination sites and phosphorylation sites responsible for the regulation of cleaved PAR-4. Further analyses of the post-translational mechanisms involved in cl.PAR-4 activity still need to be investigated to better understand the regulation of this potential tumor suppressor. By better understanding the mechanisms of PAR-4 and its cleaved form, we may be able to utilize this protein to sensitize chemoresistant endometrial cancer cells to chemotherapy. These findings may open new treatment options against endometrial cancers. Citation Format: Kevin Brasseur, Sophie Parent, François Fabi, Éric Asselin. Post-translational mechanisms related to PAR-4 regulation in endometrial cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3386. doi:10.1158/1538-7445.AM2014-3386
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
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 tête enseignante, 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 ».