Artículo
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
Autor/es | Martín Pérez, Rosa
Yerbes, Rosario Mora Molina, Rocío Cano González, Ana María Arribas, Joaquín Mazzone, Massimiliano López Rivas, Abelardo Palacios, Carmen |
Fecha de publicación | 2017 |
Fecha de depósito | 2018-12-11 |
Publicado en |
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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, ... 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. |
Identificador del proyecto | SAF2012-32824
SAF2015-64383-P BIO 778 CIBERONC ISCIII CB16/12/00421 RD12/0036/0026 RD12/0036/0042 |
Cita | Martín Pérez, R., Yerbes, R., Mora Molina, R., Cano González, A.M., Arribas, J., Mazzone, M.,...,Palacios, C. (2017). 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. Oncotarget, 8 (55), 93688-93703. |
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