β-Cryptoxanthin induced anti-proliferation and apoptosis by G0/G1 arrest and AMPK signal inactivation in gastric cancer

Eur J Pharmacol. 2019 Sep 15;859:172528. doi: 10.1016/j.ejphar.2019.172528. Epub 2019 Jul 6.

Abstract

β-Cryptoxanthin has been associated with reduced-risk of some cancers. However, the mechanisms of β-cryptoxanthin still remain unclearly understood in gastric cancer (GC). In this study, we examined the effect of β-cryptoxanthin on AMPK signal in human gastric cancer cells. AGS and SGC-7901 cells were treated with β-cryptoxanthin (0-40 μM) and AGS cells were injected in BALB/c (nu/nu) mice to analyze the effect of β-cryptoxanthin on GC. We found that β-cryptoxanthin induced inhibitory effect on the cell viability in a time- and concentration-dependent manner. The number of migrated cells and protein levels of matrix metalloproteinase (MMP) -2 and MMP-9 were obviously decreased. β-Cryptoxanthin treatment induced G0/G1 arrest, and reduced the expression of Cyclin E, Cyclin D1, cyclin-dependent kinases (CDK) of CDK4 and CDK6, and increased the expression of p53 and p21 in the two GC cells. Additionally, β-cryptoxanthin induced apoptosis and increased the expression of cleaved caspase-3, -8, -9 as well as cytochrome C (cyt C). β-Cryptoxanthin induced AMP-activated protein kinase (AMPK) signal inactivation by the down-regulation of protein kinase A (PKA), p-AMPK, eukaryotic elongation factor 2 kinase (eEF2k). Furthermore, β-cryptoxanthin inhibited tumor growth through suppressing the tumor volume and weight, inducing apoptotic cells. Besides, β-cryptoxanthin induced significant reductions of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). In conclusion, our data provide the novel evidence to understand the mechanism of anti-pcancer of β-cryptoxanthin and indicate that β-cryptoxanthin can serve as a promising chemopreventive agent against gastric cancer.

Keywords: AMPK signal; Anti-proliferation; Apoptosis; G0/G1; Gastric cancer; β-Cryptoxanthin.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Beta-Cryptoxanthin / pharmacology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • G1 Phase Cell Cycle Checkpoints / drug effects*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Male
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Resting Phase, Cell Cycle / drug effects*
  • Signal Transduction / drug effects*
  • Stomach Neoplasms / pathology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Beta-Cryptoxanthin
  • AMP-Activated Protein Kinases
  • Matrix Metalloproteinases