Abstract 824: Regulation of PAR-4 activity in chemoresistant ovarian cancer cells: A major role for the cleaved fragment in the control of apoptosis.
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 we have shown that it has all the necessary sites to induce apoptosis. In the present study, we have investigated the mechanisms regulating PAR-4 and its cleaved form in chemosensitive versus chemoresistant ovarian cancer cells. Using A2780/A2780CP ovarian cell lines (sensitive and resistant to cisplatin in vitro) and OV2295/OV2295-2 (sensitive cells obtained before treatment and cisplatin resistance acquired in vivo), we compared expression level of PAR-4 and its cleaved form (cl.PAR-4) after treatment with cisplatin. Only sensitive cancer cells have a decrease of PAR-4 level and an increase of cl.PAR-4. To further investigate mechanisms behind cl.PAR-4, we produced stable clones of A2780/A2780CP expressing cl.PAR-4-MYC using lentiviral particles. Our first observations were that, upon cisplatin treatment, cl.PAR-4-MYC protein level was increased indicating post-translational mechanisms regulating cl.PAR-4. Using proteasome inhibitor, MG-132, cl.PAR-4-MYC expression level highly increase indicating a link between cl.PAR-4 and the proteasome. We also obtained preliminary results indicating a regulation of cl.PAR-4-MYC by the MAPK pathway. Using U0126, a MEK ½ inhibitor, we were able to lower cl.PAR-4-MYC protein level and also basal cl.PAR-4. Upon cisplatin treatment in A2780-cl.PAR-4, p-ERK ½ expression increased in correlation with the increase of cl.PAR-4-MYC while in A2780-Empty cells, the level of p-ERK ½ was not influenced. We also investigated the localization of cl.PAR-4 using cytoplasmic/nuclear fractionation and harvested the culture supernatant to verify if the protein is excreted from the cancer cells. The fractionation indicates that cl.PAR-4-MYC is localized equally in both nucleus and cytoplasm. We have analyzed the supernatant and found that cl.PAR-4 is also present outside of the cell indicating an excretion/secretion mechanism of cl.PAR-4. Further analyses of the post-translational mechanisms behind cl.PAR-4 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 ovarian cancer cells. These findings may open new treatment options against women's cancers by improving their health. Citation Format: Kevin Brasseur, Sophie Parent, Éric Asselin. Regulation of PAR-4 activity in chemoresistant ovarian cancer cells: A major role for the cleaved fragment in the control of apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 824. doi:10.1158/1538-7445.AM2013-824
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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 | 0,000 |
| 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) | 0,000 | 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 ».