Abstract 2111: Regulation and localization of the cleaved form of PAR-4 in ovarian and endometrial cancers
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 cleavage of PAR-4 has been demonstrated by our laboratory and this cleaved fragment might be responsible for PAR–induced apoptosis. In the present study, we have investigated the mechanisms regulating PAR-4 expression/activity and its cleaved form in ovarian and endometrial cancer cell lines. Briefly, we used chemo-sensitive and resistant cancer cell lines in which we produced stable clones expressing the cleaved form of PAR-4 (cl.PAR-4) using lentiviral particles. Using these models, we studied the regulation of cl.PAR-4 at the protein and genomic level. Treated with cisplatin, sensitive cancer cells showed a decrease of PAR-4 and an important increase of endogenous cl.PAR-4. Using our stable clones, we observed that upon cisplatin treatment, the normally constitutively expressed cl.PAR-4 protein level was increased while the cDNA transgene was constitutively expressed, indicating a possible involvement of post-translational mechanisms. Our results indicate that degradation of our protein by the proteasome could be implicated because of the significant increase of cl.PAR-4 in the presence of a proteasome inhibitor (MG-132). PI3k could also be linked to this regulation because of an increase of cl.PAR-4 in the presence of PI3k inhibitors (LY294002, Wortmannin and BEZ235). Conversely, when using MAPK inhibitors (U0126 and PD98059), cl.PAR-4 was negatively regulated. We also investigated the localization of cl.PAR-4 using cytoplasmic/nuclear fractionationnation and immunofluorescence. The results indicated that cl.PAR-4 is mainly localized to the cytoplasm while being weakly present in the nucleus. Cisplatin treatment does not seem to influence its localization. This nuclear localization of cl.PAR-4 may have a role in its ability to induce apoptosis. Finally, bioinformatic analyses suggests possible ubiquitination and phosphorylation sites responsible for the regulation of cl.PAR-4. Further analyses of the post-translational mechanisms involved in cl.PAR-4 activity are still needed 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 target this protein to sensitize chemoresistant gynecological cancer cells to chemotherapy. Citation Format: Kevin Brasseur, Valérie Leblanc, Sophie Parent, Éric Asselin. Regulation and localization of the cleaved form of PAR-4 in ovarian and endometrial cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2111. doi:10.1158/1538-7445.AM2015-2111
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 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».