γ-Tocotrienol induced cell cycle arrest and apoptosis via activating the Bax-mediated mitochondrial and AMPK signaling pathways in 3T3-L1 adipocytes
Journal
Food and Chemical Toxicology
Journal Volume
59
Journal Volume
59
Pages
501-513
Start Page
501
End Page
513
ISSN
18736351
Date Issued
2013
Author(s)
Abstract
This study aimed to examine the anti-proliferative effects of α-, γ- and δ-tocotrienols (αT3, γT3 and δT3), and α-tocopherol on 3T3-L1 adipocytes. Results showed that compared with other vitamin E analogues, γT3 demonstrated the most potent anti-proliferative effect on 3T3-L1 cells. It significantly caused a reduction in mitochondrial membrane potential (δψm) and an increase in ROS formation, as well as inducing cell apoptosis and cell cycle arrest at S phase. Further studies showed that it down-regulated Bcl-2 and PPAR-γ expression, suppressed Akt and ERK activation and phosphorylation, and caused cytochrome c release from mitochondria to cytosol, whereas it up-regulated CD95 (APO-1/CD95) and Bax expression, and caused caspase-3 and JNK activation, PARP cleavage and AMPK phosphorylation. Pretreatments with caspase-3 (z-DEVD-fmk) and AMPK (CC) inhibitors significantly suppressed the γT3-induced ROS production and cell death. Caspase-3 inhibitor also efficiently blocked CD95 (APO-1/CD95) and Bax expression, caspase-3 activation and PARP cleavage, whereas antioxidant N-acetyl-. l-cysteine, AMPK inhibitor and AMPK siRNA effectively blocked the AMPK phosphorylation. Taken together, these results conclude that the potent anti-proliferative and anti-adipogenic effects of γT3 on 3T3-L1 adipocytes could be through the Bax-mediated mitochondrial and AMPK signaling pathways.
Subjects
3T3-L1 adipocytes
Adipogenesis
AMPK
Apoptosis
Tocotrienols
SDGs
Other Subjects
caspase 3; cytochrome c; Fas antigen; gamma tocotrienol; hydroxymethylglutaryl coenzyme A reductase kinase; mitogen activated protein kinase; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; peroxisome proliferator activated receptor gamma; protein Bax; protein kinase B; reactive oxygen metabolite; adipocyte; animal cell; apoptosis; article; cell cycle arrest; cell proliferation; cell strain; concentration response; controlled study; down regulation; drug cytotoxicity; drug targeting; enzyme inhibition; lipolysis; mitochondrial membrane potential; mitochondrial targeting signal; mouse; nonhuman; protein cleavage; protein expression; protein function; protein localization; protein phosphorylation; signal transduction; upregulation; 3T3-L1 adipocytes; Adipogenesis; AMPK; Apoptosis; Tocotrienols; 3T3-L1 Cells; Adipocytes, White; Adipogenesis; AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; Apoptosis; bcl-2-Associated X Protein; Cell Proliferation; Cell Survival; Chromans; Dietary Supplements; Down-Regulation; Membrane Potential, Mitochondrial; Mice; Mitochondria; Phosphorylation; Protein Processing, Post-Translational; Reactive Oxygen Species; RNA Interference; S Phase; Signal Transduction; Vitamin E
Type
journal article