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

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.

Autophagy mitigates ethanol-induced mitochondrial dysfunction and oxidative stress in esophageal keratinocytes

“…FOXO3 regulates transcription of oxidative phosphorylation (OXPHOS) genes in mitochondria. AMPK promotes FOXO3 translocation to mitochondria and mtDNA binding [50]. Thus, FOXO3 may contribute to maintenance of mitochondrial functions in cells surviving EtOH-induced stress conditions, warranting further study in future investigations.…”

AMP-activated protein kinase: the current landscape for drug development

“…117 ), which in turn increases the expression of several key autophagy genes including those encoding LC3, beclin 1, VPS34 and BNIP3 (REFS 118,119 ). In addition, AMPK phosphorylation has recently been reported to promote import of FOXO3 into mitochondria, where it is cleaved, allowing it to regulate mitochondrial transcription 120 . Thus, AMPK promotes mitophagy both through direct phosphorylation and activation of ULK1 and ACSS and by antagonizing mTORC1 and FOXO.…”

Mitochondrial Quality Control in Cardiomyocytes: A Critical Role in the Progression of Cardiovascular Diseases

“…SIRT3 depletion facilitates angiotensin II-induced PINK/Parkin acetylation and increases ROS generation, leading to impaired mitophagy, while the overexpression of SIRT3 enhances PINK/Parkin-dependent mitophagy, reduces ROS generation, restores vessel sprouting and tube formation, and improves cardiac function and microvascular network formation in vivo (Wei et al, 2017). Similarly, SIRT3 catalyzes the acetylation of Forkhead box protein O (FOXO) 3, which is upstream of Parkin-dependent mitophagy (Celestini et al, 2018), to maintain mitochondrial homeostasis during streptozotocininduced diabetic cardiomyopathy in vivo (Das et al, 2014). In addition, deacetylation has been reported to regulate the levels of mitochondrial metabolism proteins that localize in the mitochondrial matrix, such as superoxide dismutase (SOD) 2 (Dikalova et al, 2017), nicotinamide mononucleotide adenylyltransferase (NMNAT) 3 (Yue et al, 2016), and glycogen synthase kinase (GSK) 3β (Sundaresan et al, 2015), to protect cardiomyocytes from hypertension, hypertrophy, and cardiac fibrosis in vivo.…”