Oridonin, a novel lysine acetyltransferases inhibitor, inhibits proliferation and induces apoptosis in gastric cancer cells through p53- and caspase-3-mediated mechanisms

Oncotarget. 2016 Apr 19;7(16):22623-31. doi: 10.18632/oncotarget.8033.

Abstract

Lysine acetylation has been reported to involve in the pathogenesis of multiple diseases including cancer. In our screening study to identify natural compounds with lysine acetyltransferase inhibitor (KATi) activity, oridonin was found to possess acetyltransferase-inhibitory effects on multiple acetyltransferases including P300, GCN5, Tip60, and pCAF. In gastric cancer cells, oridonin treatment inhibited cell proliferation in a concentration-dependent manner and down-regulated the expression of p53 downstream genes, whereas p53 inhibition by PFT-α reversed the antiproliferative effects of oridonin. Moreover, oridonin treatment induced cell apoptosis, increased the levels of activated caspase-3 and caspase-9, and decreased the mitochondrial membrane potential in gastric cancer cells in a concentration-dependent manner. Caspase-3 inhibition by Ac-DEVD-CHO reversed the proapoptosis effect of oridonin. In conclusion, our study identified oridonin as a novel KATi and demonstrated its tumor suppressive effects in gastric cancer cells at least partially through p53-and caspase-3-mediated mechanisms.

Keywords: antiproliferation; apoptosis; gastric cancer; lysine acetyltransferase inhibitor; oridonin.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Diterpenes, Kaurane / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Lysine Acetyltransferases / antagonists & inhibitors*
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • Diterpenes, Kaurane
  • Enzyme Inhibitors
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • oridonin
  • Lysine Acetyltransferases
  • CASP3 protein, human
  • Caspase 3