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

• DOI: 10.1038/s41419-018-0336-0
• Publication Date: 2018-02-14T12:32:58Z
• Authors: Valentina Celestini; Tugsan Tezil; Luciana Russo; Candida Fasano; Paola Sanese; Giovanna Forte; Alessia Peserico; Martina Lepore Si...; Giovanna Longo; Domenico De Rasmo; Anna Signorile; Raffaella Maria G...; Natasha Scialpi; Mineko Terao; Enrico Garattini; Tiziana Cocco; Gaetano Villani; Antonio Moschetta; Valentina Grossi; Cristiano Simone
• Keywords: 0301 basic medicine; Cell Survival; Antineoplastic Agents; Apoptosis; AMP-Activated Protein Kinases; Irinotecan; Article; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Extracellular Signal-Regulated MAP Kinases; Cell Nucleus; Gene Editing; Foxo3A; mitochondrial; carcinogenesis; Non previste; Forkhead Box Protein O3; AMP-Activated Protein Kinases; Animals; Antineoplastic Agents; Apoptosis; CRISPR-Cas Systems; Cell Line, Tumor; Cell Nucleus; Cell Survival; Cisplatin; Extracellular Signal-Regulated MAP Kinases; Fluorouracil; Forkhead Box Protein O3; Gene Editing; Genome, Mitochondrial; HEK293 Cells; Humans; Irinotecan; MAP Kinase Kinase Kinases; Metformin; Mice; Mice, Inbred C57BL; Mitochondria; NIH 3T3 Cells; Phosphorylation; Signal Transduction; Stress, Physiological; Gene Expression Regulation, Neoplastic; MAP Kinase Kinase Kinases; Metformin; 3. Good health; mitochondria; Gene Expression Regulation, Neoplastic; HEK293 Cells; Genome, Mitochondrial; Fluorouracil; CRISPR-Cas Systems; Cisplatin

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 a key determinant of homeostasis, playing dual role in survival/death response to metabolic stress therapeutics. We recently described novel arm the AMPK-FoxO3A axis cells upon nutrient shortage. Here, we show that metabolically stressed cells, recruited mitochondria through activation MEK/ERK AMPK, which phosphorylate serine 12 30, respectively, on N-terminal domain. Subsequently, imported cleaved reach DNA, where it activates expression genome support metabolism. Using −/− generated CRISPR/Cas9 editing system reconstituted mutants being impaired their nuclear or subcellular localization, promotes survival stress. In treated chemotherapeutic agents, accumulation into promoted MEK/ERK-dependent manner, while was required apoptosis induction by metformin. Elucidation vs. homeostasis might help devise therapeutic strategies selectively disable prosurvival activity.