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.
Highlights
Carcinogenesis is a multistep process by which normal cells evolve to a neoplastic state by acquiring a succession of cancer hallmarks[1]
To ascertain whether it could undergo posttranslational processing similar to other nuclearencoded mitochondrial proteins[21], we purified mitochondria from several normal and cancer cell lines of different origin cultured under high (HG) or low (LG) glucose conditions and performed a proteinase K (PK) protection assay to detect proteins localized at the outer membrane or inside the mitochondria
In LG, antiFoxO3A antibodies revealed the presence of two bands in the whole mitochondria fraction, while after PK treatment only the 70 kDa band was detected into the organelles (Fig. 1b, d, e and Supplementary Figure S1b)
Summary
Carcinogenesis is a multistep process by which normal cells evolve to a neoplastic state by acquiring a succession of cancer hallmarks[1]. Oncology (DIMO), University of Bari Aldo Moro, Bari 70124, Italy 2Department of Biochemistry and Molecular Pharmacology/Laboratory of Molecular Biology, IRCCS - Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milano 20156, Italy by the balance between these newly acquired oncogenic features and pre-existing cellular functions Paradigmatic in this regard is the reprogramming of energy metabolism, where normal cellular processes providing increased energy production, macromolecular biosynthesis, and. Celestini et al Cell Death and Disease (2018)9:231 Consistent with this view, proteins that have been classically considered as tumor suppressors are sometimes required to be functional for full malignant transformation. This is the case for FoxO3A, which can be both friend and foe to cancer cells depending on the cellular context[8,9,10]
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