2. Academic Validation
  3. Uncoupling FoxO3A mitochondrial and nuclear functions in cancer cells undergoing metabolic stress and chemotherapy

Uncoupling FoxO3A mitochondrial and nuclear functions in cancer cells undergoing metabolic stress and chemotherapy

  • Cell Death Dis. 2018 Feb 14;9(2):231. doi: 10.1038/s41419-018-0336-0.
Valentina Celestini 1 2,  Tugsan Tezil 1,  Luciana Russo 3,  Candida Fasano 3,  Paola Sanese 1,  Giovanna Forte 3,  Alessia Peserico 1,  Martina Lepore Signorile 1 4,  Giovanna Longo 1,  Domenico De Rasmo 5,  Anna Signorile 6,  Raffaella Maria Gadaleta 7 8,  Natasha Scialpi 8,  Mineko Terao 2,  Enrico Garattini 2,  Tiziana Cocco 6,  Gaetano Villani 6,  Antonio Moschetta 8,  Valentina Grossi 9,  Cristiano Simone 10 11
Affiliations

Affiliations

  • 1 Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari Aldo Moro, Bari, 70124, Italy.
  • 2 Department of Biochemistry and Molecular Pharmacology/Laboratory of Molecular Biology, IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri', Milano, 20156, Italy.
  • 3 Medical Genetics, National Institute for Gastroenterology, IRCCS 'S. de Bellis', Castellana Grotte (Ba), 70013, Italy.
  • 4 Department of Molecular Medicine, Sapienza University of Rome, 00161, Rome, Italy.
  • 5 Institute of Biomembranes and Bioenergetics, National Research Council (CNR), Bari, 70126, Italy.
  • 6 Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, 70124, Italy.
  • 7 Division of Digestive Diseases, Department of Surgery and Cancer, Imperial College London, Queen Elizabeth the Queen Mother Wing (QEQM), London, W2 1NY, UK.
  • 8 Medicina Interna Universitaria Frugoni', Department of Interdisciplinary Medicine, University of Bari Aldo Moro, Bari, 70124, Italy.
  • 9 Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari Aldo Moro, Bari, 70124, Italy. grossi.labsimone@gmail.com.
  • 10 Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari Aldo Moro, Bari, 70124, Italy. cristiano.simone@uniba.it.
  • 11 Medical Genetics, National Institute for Gastroenterology, IRCCS 'S. de Bellis', Castellana Grotte (Ba), 70013, Italy. cristiano.simone@uniba.it.
PMID: 29445193 DOI: 10.1038/s41419-018-0336-0
Abstract

While aberrant Cancer cell growth is frequently associated with altered biochemical metabolism, normal mitochondrial functions are usually preserved and necessary for full malignant transformation. The transcription factor FoxO3A is a key determinant of Cancer cell homeostasis, playing a dual role in survival/death response to metabolic stress and Cancer therapeutics. We recently described a novel mitochondrial arm of the AMPK-FoxO3A axis in normal cells upon nutrient shortage. Here, we show that in metabolically stressed Cancer cells, FoxO3A is recruited to the mitochondria through activation of MEK/ERK and AMPK, which phosphorylate serine 12 and 30, respectively, on FoxO3A N-terminal domain. Subsequently, FoxO3A is imported and cleaved to reach mitochondrial DNA, where it activates expression of the mitochondrial genome to support Mitochondrial Metabolism. Using FoxO3A-/- Cancer cells generated with the CRISPR/Cas9 genome editing system and reconstituted with FoxO3A mutants being impaired in their nuclear or mitochondrial subcellular localization, we show that mitochondrial FoxO3A promotes survival in response to metabolic stress. In Cancer cells treated with chemotherapeutic agents, accumulation of FoxO3A into the mitochondria promoted survival in a MEK/ERK-dependent manner, while mitochondrial FoxO3A was required for Apoptosis induction by metformin. Elucidation of FoxO3A mitochondrial vs. nuclear functions in Cancer cell homeostasis might help devise novel therapeutic strategies to selectively disable FoxO3A prosurvival activity.

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