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Página principal > Artículos > Artículos publicados > Oncogenic p95HER2/611CTF primes human breast epithelial cells for metabolic stress-induced down-regulation of FLIP and activation of TRAIL-R/Caspase-8-dependent apoptosis |
Fecha: | 2017 |
Resumen: | Oncogenic transformation triggers reprogramming of cell metabolism, as part of the tumorigenic process. However, metabolic reprogramming may also increase the sensitivity of transformed cells to microenvironmental stress, at the early stages of tumor development. Herein, we show that transformation of human breast epithelial cells by the p95HER2/611CTF oncogene markedly sensitizes these cells to metabolic stress induced by the simultaneous inhibition of glucose and glutamine metabolism. In p95HER2/611CTF-transformed cells, metabolic stress activates a TNF related apoptosis-inducing ligand (TRAIL)-R and caspase-8-dependent apoptotic process that requires prior down-regulation of cellular FLICE-like inhibitor protein (c-FLIP) levels. Importantly, sustained mTOR activation is involved in FLIP down-regulation and apoptosis induced by metabolic stress. In vivo experiments in immunodeficient mice demonstrate a requirement for caspase-8 in restraining primary tumor growth of xenografts with p95HER2/611CTF-transformed cells. Collectively, these data define a critical role of the extrinsic pathway of apoptosis in the control of tumor initiation by microenvironmental cues. |
Ayudas: | Ministerio de Economía y Competitividad SAF2012-32824 Ministerio de Economía y Competitividad SAF2015-64383 Instituto de Salud Carlos III CB16-12-00421 |
Nota: | Altres ajuts: This work was supported by grants from Junta de Andalucía Excellence Program (BIO 778) and Red Temática de Investigación Cooperativa en Cáncer (RD12/0036/0026 to ALR and RD12/0036/0042 to JA) and the European Community through the regional development funding program (FEDER). |
Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Lengua: | Anglès |
Documento: | Article ; recerca ; Versió publicada |
Materia: | P95HER2/611CTF ; Metabolic stress ; TRAIL-R ; FLIP ; MTOR |
Publicado en: | Oncotarget, Vol. 8 (october 2017) , p. 93688-93703, ISSN 1949-2553 |
16 p, 2.6 MB |