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

Valentina Celestini, Tugsan Tezil, Luciana Russo, Candida Fasano, Paola Sanese, Giovanna Forte, Alessia Peserico, Martina Lepore Signorile, Giovanna Longo, Domenico De Rasmo, Anna Signorile, Raffaella Maria Gadaleta, Natasha Scialpi, Mineko Terao, Enrico Garattini, Tiziana Cocco, Gaetano Villani, Antonio Moschetta, Valentina Grossi, Cristiano Simone

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)231
JournalCell Death and Disease
Volume9
Issue number2
DOIs
Publication statusPublished - Feb 14 2018

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Physiological Stress
Drug Therapy
Neoplasms
AMP-Activated Protein Kinases
Mitogen-Activated Protein Kinase Kinases
Mitochondria
Homeostasis
Clustered Regularly Interspaced Short Palindromic Repeats
Mitochondrial Genome
Metformin
Mitochondrial DNA
Serine
Transcription Factors
Apoptosis
Food
Therapeutics
Growth

Cite this

Uncoupling FoxO3A mitochondrial and nuclear functions in cancer cells undergoing metabolic stress and chemotherapy. / Celestini, Valentina; Tezil, Tugsan; Russo, Luciana; Fasano, Candida; Sanese, Paola; Forte, Giovanna; Peserico, Alessia; Lepore Signorile, Martina; Longo, Giovanna; De Rasmo, Domenico; Signorile, Anna; Gadaleta, Raffaella Maria; Scialpi, Natasha; Terao, Mineko; Garattini, Enrico; Cocco, Tiziana; Villani, Gaetano; Moschetta, Antonio; Grossi, Valentina; Simone, Cristiano.

In: Cell Death and Disease, Vol. 9, No. 2, 14.02.2018, p. 231.

Research output: Contribution to journalArticle

Celestini, V, Tezil, T, Russo, L, Fasano, C, Sanese, P, Forte, G, Peserico, A, Lepore Signorile, M, Longo, G, De Rasmo, D, Signorile, A, Gadaleta, RM, Scialpi, N, Terao, M, Garattini, E, Cocco, T, Villani, G, Moschetta, A, Grossi, V & Simone, C 2018, 'Uncoupling FoxO3A mitochondrial and nuclear functions in cancer cells undergoing metabolic stress and chemotherapy', Cell Death and Disease, vol. 9, no. 2, pp. 231. https://doi.org/10.1038/s41419-018-0336-0
Celestini, Valentina ; Tezil, Tugsan ; Russo, Luciana ; Fasano, Candida ; Sanese, Paola ; Forte, Giovanna ; Peserico, Alessia ; Lepore Signorile, Martina ; Longo, Giovanna ; De Rasmo, Domenico ; Signorile, Anna ; Gadaleta, Raffaella Maria ; Scialpi, Natasha ; Terao, Mineko ; Garattini, Enrico ; Cocco, Tiziana ; Villani, Gaetano ; Moschetta, Antonio ; Grossi, Valentina ; Simone, Cristiano. / Uncoupling FoxO3A mitochondrial and nuclear functions in cancer cells undergoing metabolic stress and chemotherapy. In: Cell Death and Disease. 2018 ; Vol. 9, No. 2. pp. 231.
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N2 - 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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