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 Martin-Perez 1, 2, 3 , Rosario Yerbes 1 , Rocio Mora-Molina 1 , Ana Cano-Gonzalez 1 , Joaquin Arribas 4, 5, 6, 7 , Massimiliano Mazzone 2, 3 , Abelardo Lopez-Rivas 1, 7 and Carmen Palacios 1 1 Centro Andaluz de Biologia Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Sevilla, Spain 2 Lab of Tumor Inflammation and Angiogenesis, VIB, Leuven, Belgium 3 Lab of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium 4 Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain 5 Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain 6 Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Spain 7 Centro de Investigacion Biomedica en Red-Oncologia (CIBERONC), Carlos III Health Institute, Madrid, Spain Correspondence to: Carmen Palacios, email: carmen.palacios@cabimer.es Abelardo Lopez-Rivas, email: abelardo.lopez@cabimer.es Keywords: p95HER2/611CTF, metabolic stress, TRAIL-R, FLIP, mTOR Received: January 10, 2017      Accepted: September 16, 2017      Published: October 03, 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.