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
Martín-Pérez, Rosa (KU Leuven. Department of Oncology)
Yerbes, Rosario (Centro Andaluz de Biología Molecular y Medicina Regenerativa)
Mora-Molina, Rocío (Centro Andaluz de Biología Molecular y Medicina Regenerativa)
Cano-González, Ana (Centro Andaluz de Biología Molecular y Medicina Regenerativa)
Arribas, Joaquín V (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Mazzone, Massimiliano (KU Leuven. Department of Oncology)
López-Rivas, Abelardo (Centro de Investigación Biomédica en Red de Cáncer)
Palacios, Carmen (Centro Andaluz de Biología Molecular y Medicina Regenerativa)

Data:	2017
Resum:	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.
Ajuts:	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).
Drets:	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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	P95HER2/611CTF ; Metabolic stress ; TRAIL-R ; FLIP ; MTOR
Publicat a:	Oncotarget, Vol. 8 (october 2017) , p. 93688-93703, ISSN 1949-2553

DOI: 10.18632/oncotarget.21458
PMID: 29212182

16 p, 2.6 MB

El registre apareix a les col·leccions:
Articles > Articles de recerca
Articles > Articles publicats