Abstract A097: Inhibition of the Na+/H+ exchanger (NHE1) increases susceptibility to paclitaxel in invasive breast cancer cells
Notice bibliographique
Résumé
Abstract The pH gradient in normal cells is tightly controlled by the activity of various pH regulatory membrane proteins including the Na+/H+ exchanger, NHE1. NHE1 becomes constitutively active in a neoplastic milieu, dysregulating pH homeostasis and altering the survival, differentiation, and proliferation of cells, thus causing them to become tumorigenic. In breast cancer cells, cytoplasmic alkalinization as a result of NHE1 hyper-activity results in an acidic tumor microenvironment that facilitates aggressive cellular proliferation, migration, and invasion leading to tumor metastasis. The pathophysiological role of NHE1 in tumor progression with regards to ion flux is well known, however, the manipulation of pH in and around tumor cells has only recently been considered as a strategy in augmenting cancer therapy. We studied the effect of NHE1 inhibitors EMD87580 ((2-methyl-4,5-di-(methylsulfonyl)-benzoyl)-guanidine) and HMA (5-(N, N-hexamethylene)-amiloride), either alone or in combination with paclitaxel (Taxol), on NHE1 exchanger activity, cell viability, proliferation, migration, and invasive potential, in a highly invasive breast cancer cell line MDA MB 231. We found that cells treated with EMD or HMA in combination with paclitaxel at low doses (0.1nM to 1nM), were significantly more susceptible to cell death than cells treated with paclitaxel or inhibitors alone. While no discernible differences between treatments were observed in cell proliferation rates, a significant reduction in the rate of migration and invasion was observed in cells treated with paclitaxel and either EMD or HMA. To highlight the importance of NHE1 function, we also generated an MDA-MB-231NHE1- knockout cell line for comparison with the wild-type cells that endogenously express NHE1. The NHE1 knockout cell line showed no demonstrable Na+/H+ exchange activity, and much lower rates of proliferation, migration and invasion compared to wild-type cells. Our results demonstrate, for the first time, that inhibition of NHE1 potentially increases the susceptibility of invasive breast cancer cells to paclitaxel-mediated cell death at doses much lower than the established IC50 of paclitaxel in MDA MB 231 cells. Since pH regulation appears to play an integral role in the switch from a normal to a neoplastic microenvironment, these data lend further credence to the importance of NHE1 as a potential target in breast cancer chemotherapy. Supported by the Canadian Breast Cancer Foundation. Citation Format: Schammim Ray Amith, Jodi Marie Wilkinson, Larry Fliegel. Inhibition of the Na+/H+ exchanger (NHE1) increases susceptibility to paclitaxel in invasive breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A097.
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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 | 0,000 | 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) | 0,000 | 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 ».