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Uncoupling FoxO3A mitochondrial and nuclear functions in cancer cells undergoing metabolic stress and chemotherapy.
- Source :
-
Cell death & disease [Cell Death Dis] 2018 Feb 14; Vol. 9 (2), pp. 231. Date of Electronic Publication: 2018 Feb 14. - Publication Year :
- 2018
-
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 <superscript>-/-</superscript> 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.
- Subjects :
- AMP-Activated Protein Kinases genetics
AMP-Activated Protein Kinases metabolism
Animals
Apoptosis drug effects
Apoptosis genetics
CRISPR-Cas Systems
Cell Line, Tumor
Cell Nucleus drug effects
Cell Survival
Cisplatin pharmacology
Extracellular Signal-Regulated MAP Kinases genetics
Extracellular Signal-Regulated MAP Kinases metabolism
Fluorouracil pharmacology
Forkhead Box Protein O3 metabolism
Gene Editing
Genome, Mitochondrial
HEK293 Cells
Humans
Irinotecan pharmacology
MAP Kinase Kinase Kinases genetics
MAP Kinase Kinase Kinases metabolism
Metformin pharmacology
Mice
Mice, Inbred C57BL
Mitochondria drug effects
Mitochondria genetics
NIH 3T3 Cells
Phosphorylation
Signal Transduction
Stress, Physiological drug effects
Stress, Physiological genetics
Antineoplastic Agents pharmacology
Cell Nucleus metabolism
Forkhead Box Protein O3 genetics
Gene Expression Regulation, Neoplastic
Mitochondria metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 9
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 29445193
- Full Text :
- https://doi.org/10.1038/s41419-018-0336-0