γ-Tocotrienol induced cell cycle arrest and apoptosis via activating the Bax-mediated mitochondrial and AMPK signaling pathways in 3T3-L1 adipocytes

Food Chem Toxicol. 2013 Sep;59:501-13. doi: 10.1016/j.fct.2013.06.011. Epub 2013 Jun 29.

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.

Keywords: 3T3-L1 adipocytes; AMPK; Adipogenesis; Apoptosis; Tocotrienols.

Publication types

  • Comparative Study

MeSH terms

  • 3T3-L1 Cells
  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / chemistry
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Adipocytes, White / cytology
  • Adipocytes, White / enzymology
  • Adipocytes, White / metabolism*
  • Adipogenesis*
  • Animals
  • Anti-Obesity Agents / metabolism
  • Apoptosis*
  • Cell Proliferation
  • Cell Survival
  • Chromans / antagonists & inhibitors
  • Chromans / metabolism*
  • Dietary Supplements*
  • Down-Regulation
  • Membrane Potential, Mitochondrial
  • Mice
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • RNA Interference
  • Reactive Oxygen Species / agonists
  • Reactive Oxygen Species / metabolism
  • S Phase
  • Signal Transduction*
  • Vitamin E / analogs & derivatives*
  • Vitamin E / antagonists & inhibitors
  • Vitamin E / metabolism
  • bcl-2-Associated X Protein / agonists
  • bcl-2-Associated X Protein / metabolism

Substances

  • Anti-Obesity Agents
  • Bax protein, mouse
  • Chromans
  • Reactive Oxygen Species
  • bcl-2-Associated X Protein
  • Vitamin E
  • plastochromanol 8
  • AMP-Activated Protein Kinases