Abstract 3792: PAPSS1 (3’-phosphoadenosine 5’-phosphosulfate synthase 1) inhibition sensitizes non-small cell lung cancer to cisplatin treatment <i>in vivo</i>
Notice bibliographique
Résumé
Abstract We previously reported that 3’-phosphoadenosine-5’-phosphosulfate (PAPS) synthase 1 (PAPSS1), an enzyme that synthesizes the biologically active form of sulfate (PAPS) for all sulfation reactions, is a novel therapeutic target that when suppressed enhances the activity of multiple DNA damaging agents in NSCLC cells. PAPSS1 was the lead hit in a synthetic lethal screen completed using chemotherapy-naive NSCLC cells exposed to the IC10 of cisplatin (CDDP). PAPSS1 silencing was more effective in potentiating CDDP activity than our positive control (BRACA2). Here, we evaluated PAPSS1 as a CDDP-sensitizing target in three different model systems: 3D spheroids, zebrafish xenografts, and a mouse xenograft model. siRNA-transfected A549 cells were seeded in round bottom ultra-low attachment plates for spheroid formation. Spheroids were formed over a period of three days and then treated with CDDP. The spheroids were imaged using the IncuCyte ZOOM® Live Cell Imaging system every 3 hours for 8 days to monitor changes in spheroid size. To evaluate PAPSS1 in zebrafish, transfected A549 cells were microinjected into the yolk sack of zebrafish embryos and then maintained in CDDP-containing media for 48 hours. The human cells were harvested from 20 fish per treatment group and counted to determine the change in cell number as a measure of tumor growth in vivo. For mouse studies, RAG2M mice were inoculated subcutaneously with 5×106 parental, non-targeting shRNA, or shPAPSS1-expressing A549 cells. The mice were treated 7 days later with 3 mg/kg CDDP (IV, Q4Dx3). Tumor size was measured using an electronic caliper and tumor volumes were calculated using the equation (lxw2)/2. PAPSS1-silenced cells formed spheroids of comparable size as the scramble control. CDDP (12.5μM) was effective against both control and PAPSS1-silenced spheroids with a reduction of 31% and 46% in spheroid size, respectively. PAPSS1-knockdown spheroids were significantly more sensitive to CDDP even when added at an 8-fold lower dose (1.56 μM). At this concentration, the control spheroids grew about 37% in size while the size of the PAPSS1-silenced spheroids was reduced by 21% (p<0.0001). In zebrafish, the number of A549 cells was reduced by approximately 50% with the combination of PAPSS1 knockdown and CDDP treatment relative to non-silencing, CDDP-treated controls. In mice, tumor development was significantly delayed in the shPAPSS1 group relative to both parental (p = 0.008) and non-targeting shRNA (p = 0.026) controls following CDDP treatment. Our study demonstrates for the first time that PAPSS1 knockdown enhances CDDP treatment in vivo. To pursue PAPSS1 as a therapeutic target, a small molecule inhibitor screen is warranted. The availability of a small molecule inhibitor will be essential to understand how PAPSS1 inhibition sensitizes cancer cells (but not normal cells) to DNA damaging agents. Citation Format: Ada W.Y. Leung, Chansey J. Veinotte, Nicole Melong, Ian Backstrom, Corinna Warburton, Edie Dullaghan, Jason N. Berman, Marcel B. Bally. PAPSS1 (3’-phosphoadenosine 5’-phosphosulfate synthase 1) inhibition sensitizes non-small cell lung cancer to cisplatin treatment in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3792.
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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 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 ».