Back to Search Start Over

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

Authors :
Ana Cano-González
Rocío Mora-Molina
Rosario Yerbes
Carmen Palacios
Massimiliano Mazzone
Joaquín Arribas
Rosa Martín-Pérez
Abelardo López-Rivas
Red Temática de Investigación Cooperativa en Cáncer (España)
Ministerio de Economía y Competitividad (España)
Instituto de Salud Carlos III
European Commission
Junta de Andalucía
Source :
Digital.CSIC. Repositorio Institucional del CSIC, instname, Dipòsit Digital de Documents de la UAB, Universitat Autònoma de Barcelona, Oncotarget, idUS. Depósito de Investigación de la Universidad de Sevilla
Publication Year :
2017
Publisher :
Impact Journals, LLC, 2017.

Abstract

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.<br />This work was supported by grants from Ministerio de Economía y Competitividad (SAF2012-32824 and SAF2015-64383-P), Junta de Andalucía Excellence Program (BIO 778), CIBERONC ISCIII CB16/12/00421 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).

Details

ISSN :
19492553
Volume :
8
Database :
OpenAIRE
Journal :
Oncotarget
Accession number :
edsair.doi.dedup.....544d23e929189767425cc8da782fe8a7
Full Text :
https://doi.org/10.18632/oncotarget.21458