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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
- 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).
- Subjects :
- EXPRESSION
0301 basic medicine
TRAIL-R
FLIP
Angiogenesis
TUMOR-CELLS
p95HER2/611CTF
TRAIL
Inflammation
Tumor initiation
UP-REGULATION
Caspase 8
PATHWAY
03 medical and health sciences
0302 clinical medicine
Medicine
Metabolic stress
PI3K/AKT/mTOR pathway
Science & Technology
RECEPTOR
P95HER2/611CTF
Oncogene
UNFOLDED-PROTEIN-RESPONSE
MTOR
business.industry
DEATH
Cell Biology
CANCER
GLUTAMINE
030104 developmental biology
Oncology
Apoptosis
030220 oncology & carcinogenesis
Immunology
Cancer research
Tumor necrosis factor alpha
medicine.symptom
business
Life Sciences & Biomedicine
Research Paper
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....544d23e929189767425cc8da782fe8a7
- Full Text :
- https://doi.org/10.18632/oncotarget.21458