Foxc2 enhances proliferation and inhibits apoptosis through activating Akt/mTORC1 signaling pathway in mouse preadipocytes

Abstract

found in various organs and tissues, such as the cardiac system, mammary gland, liver, and adipose tissue . In general, Foxc2 plays important roles in the regulation of cell growth, proliferation, differentiation, apoptosis, and energy metabolism. Mice lacking Foxc2 die during embryogenesis or perinatally and exhibit aortic arch and skeletal defects ( 1-4 ). Previous studies have shown that, in adipocytes, either a high-calorie diet or insulin induces Foxc2 expression, suggesting that Foxc2 is an important metabolic regulator of mitochondrial morphology and metabolism ( 5, 6 ). In 3T3-L1 preadipocytes, Foxc2 extensively decreased the expression of CCAAT/enhancer-binding protein ␣ (C/EBP ␣ ), PPAR ␥ , adiponectin, perilipin, and adipocyte protein 2 (aP2), so as to prevent preadipocytes from differentiating into mature adipocytes with lipid droplets ( 7 ). Recent studies mostly focus on the regulation role of Foxc2 on trans-differentiation of intra-abdominal white adipose tissue to brown fat-like tissue in transgenic mice that overexpress Foxc2, and those mice that present a lean and insulin-sensitive phenotype and are able to counteract metabolic disorders associated with obesity, including type 2 diabetes and hyperlipidemia ( 6,8 ). The Foxc2 level could be increased by a high-fat diet (HFD), which counteracted most of the symptoms associated with obesity, including hypertriglyceridemia and diet-induced insulin resistance, and these results suggest a potentially therapeutic role of Foxc2 in the protection against type 2 diabetes ( 6, 9-13 ).Foxc2 plays an important role in cell proliferation ( 14 ). Research on the regulatory role of Foxc2 in muscle regeneration and osteogenesis has shown that downregulation of endogenous Foxc2 expression in undifferentiated C2C12 myoblasts decreases cell proliferation, whereas forced expression of Foxc2 enhanced myoblast proliferation Abstract Forkhead box C2 (Foxc2) protein is a transcription factor in regulation of development, metabolism, and immunology. However, the regulatory mechanisms of Foxc2 on proliferation and apoptosis of preadipocytes are unclear. In this study, we found that high-fat-diet-induced obesity elevated the expression of Foxc2 and cyclin E after 6 weeks. Additionally, Foxc2 suppressed preadipocyte differentiation, increased cell counts and augmented G1-S transition of preadipocytes, along with the elevation of cyclin E expression and the reduction levels of p27 and p53 . Furthermore, Foxc2 knockdown reduced early apoptotic cells with accompanying reduction of mitochondrial membrane potential and increased fragmentation of genomic DNA. We show that Foxc2 reduces the expression of Bax, caspase-9, and caspase-3 in both serum-starved and palmitic acidinduced cell apoptotic models, which confi rms the antiapoptotic role of Foxc2. Moreover, the protein kinase B (Akt)/ mammalian target of rapamycin (mTOR)C1 signaling pathway and the ERK/mTORC1 signaling pathway were activated along with preadipocyte proliferation in response to Foxc2 overexpression, whereas apo...

Elevated FOXC2 Expression Promotes Invasion of HCC Cell Lines and is Associated with Poor Prognosis in Hepatocellular Carcinoma

“…The molecular mechanism behind this correlation was shown to be that FOXC2 downregulates p120-catenin, which directly suppresses the promoter activity of E-cadherin [21]. FOXC2 has been reported to enhance AKT activity to promote cell proliferation and invasion [13, 22, 23]. In our study, we found that FOXC2 is upregulated in HCC tissues and that high FOXC2 expression is correlated with poor prognosis, suggesting that FOXC2 contributes to the acquisition of the aggressive properties of HCC cells.…”

α-MSH and Foxc2 promote fatty acid oxidation through C/EBPβ negative transcription in mice adipose tissue

“…Our previous studies found Foxc2 enhanced mice pre-adipocytes proliferation and inhibited apoptosis via activating Akt/mTORC1 signaling pathway23. Foxc2 stimulates osteogenic differentiation and inhibits adipogenic differentiation in bone marrow mesenchymal stem cells, and in white adipocytes2425.…”

A 2D-QSAR and Grid-Independent Molecular Descriptor (GRIND) Analysis of Quinoline-Type Inhibitors of Akt2: Exploration of the Binding Mode in the Pleckstrin Homology (PH) Domain

“…The activation of Akt facilitates growth factor-mediated cell survival by inhibiting apoptosis via the phosphorylation and inactivation of various pro-apoptotic signals including Bcl-2-associated death (BAD) [5] and Forkhead box O (FOXOs) [6, 7], and promotes cell proliferation by phosphorylation and inhibition of the tumour suppressor tuberous sclerosis complex 2 (TSC2) and the activation of mammalian target of rapamycin complex 1 (mTORC1) [8, 9]. Additionally, it has been reported that Akt is also involved in the activation of various oncogenic signalling pathways such as Nuclear factor kappa B (NF-κB), c-myelocytomatosis (c-Myc), Vascular endothelial growth factor (VEGF) and Cyclin D, thus acting as a central regulator of various cellular functions including cell growth, survival, and metabolism [10].…”