Research Papers:

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

Rosa Martín-Pérez, Rosario Yerbes, Rocío Mora-Molina, Ana Cano-González, Joaquín Arribas, Massimiliano Mazzone, Abelardo López-Rivas and Carmen Palacios _

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Oncotarget. 2017; 8:93688-93703. https://doi.org/10.18632/oncotarget.21458

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Rosa Martín-Pérez1,2,3, Rosario Yerbes1, Rocío Mora-Molina1, Ana Cano-González1, Joaquín Arribas4,5,6,7, Massimiliano Mazzone2,3, Abelardo López-Rivas1,7 and Carmen Palacios1

1Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Sevilla, Spain

2Lab of Tumor Inflammation and Angiogenesis, VIB, Leuven, Belgium

3Lab of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium

4Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

5Department of Biochemistry and Molecular Biology, Universitat Autónoma de Barcelona, Campus de la UAB, Bellaterra, Spain

6Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

7Centro de Investigación Biomédica en Red-Oncología (CIBERONC), Carlos III Health Institute, Madrid, Spain

Correspondence to:

Carmen Palacios, email: [email protected]

Abelardo López-Rivas, email: [email protected]

Keywords: p95HER2/611CTF, metabolic stress, TRAIL-R, FLIP, mTOR

Received: January 10, 2017     Accepted: September 16, 2017     Published: October 03, 2017


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.

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