Résumé
Understanding the mechanisms responsible for the resistance against chemotherapy-induced cell death is still of great interest since the number of patients with cancer increases and relapse is commonly observed. Indeed, the development of hypoxic regions as well as UPR (unfolded protein response) activation is known to promote cancer cell adaptive responses to the stressful tumor microenvironment and resistance against anticancer therapies. Therefore, the impact of UPR combined to hypoxia on autophagy and apoptosis activation during taxol exposure was investigated in MDA-MB-231 and T47D breast cancer cells. The results showed that taxol rapidly induced UPR activation and that hypoxia modulated taxol-induced UPR activation differently according to the different UPR pathways (PERK, ATF6, and IRE1α). The putative involvement of these signaling pathways in autophagy or in apoptosis regulation in response to taxol exposure was investigated. However, while no link between the activation of these three ER stress sensors and autophagy or apoptosis regulation could be evidenced, results showed that ATF4 activation, which occurs independently of UPR activation, was involved in taxol-induced autophagy completion. In addition, an ATF4-dependent mechanism leading to cancer cell adaptation and resistance against taxol-induced cell death was evidenced. Finally, our results demonstrate that expression of ATF4, in association with hypoxia-induced genes, can be used as a biomarker of a poor prognosis for human breast cancer patients supporting the conclusion that ATF4 might play an important role in adaptation and resistance of breast cancer cells to chemotherapy in hypoxic tumors.
langue originale | Anglais |
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Pages (de - à) | 1-14 |
Nombre de pages | 14 |
journal | International Journal of Biochemistry and Cell Biology |
Volume | 62 |
Date de mise en ligne précoce | 24 févr. 2015 |
Les DOIs | |
Etat de la publication | Publié - 2015 |
Empreinte digitale
Examiner les sujets de recherche de « Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia. ATF4 activation regulates autophagy and inhibits apoptosis ». Ensemble, ils forment une empreinte digitale unique.Équipement
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Génétique - génomique
Gillet, N. (!!Manager)
Plateforme technologique Genetique et genomiqueEquipement/installations: Plateforme technolgique
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Morphologie - Imagerie
Cecchet, F. (!!Manager) & Renard, H.-F. (!!Manager)
Plateforme technologique Morphologie, imagerieEquipement/installations: Plateforme technolgique