Naringenin causes ASK1-induced apoptosis via reactive oxygen species in human pancreatic cancer cells

Food Chem Toxicol. 2017 Jan;99:1-8. doi: 10.1016/j.fct.2016.11.008. Epub 2016 Nov 9.

Abstract

Naringenin, one of the most abundant flavonoids in natural citrus fruits, has been investigated for its ability to inhibit growth of breast, colon, gastric and prostate cancer cells. However, naringenin-induced cell death in pancreatic cancer is not well understood. Therefore, we analyzed the naringenin-induced apoptosis mechanism using human pancreatic cancer SNU-213 cells. Annexin V+/PI + marked cells increased from 5.10% to 8.29%, 25.06% and 35.31% in response to treatment with 200, 400, and 600 μM naringenin, respectively. Two-dimensional electrophoresis to identify possible target-related proteins of naringenin-induced apoptosis revealed seven proteins. Among these, the expression of peroxiredoxin-1 (Prdx-1), which modulates redox homeostasis of cells, was decreased. To obtain a broad understanding of the interactive mechanism of naringenin and Prdx-1, we observed changes in reactive oxygen species (ROS) in naringenin-treated SNU-213 cells. The ROS levels were 130.02 ± 20.21%, 182.04 ± 5.39%, and 237.21 ± 12.71% in response to 200, 400, and 600 μM naringenin treatment, respectively. Increases in ROS were followed by up-regulation of apoptosis signal-regulation kinase 1 (ASK1). Moreover, the JNK, p38 and p53 proteins were upregulated. Overall, the results of this study suggest that naringenin causes ASK1-induced apoptosis mediated by ROS.

Keywords: Apoptosis signal-regulation kinase 1; Naringenin; Pancreatic cancer; Peroxiredoxin-1; Reactive oxygen species.

MeSH terms

  • Apoptosis / drug effects*
  • Blotting, Western
  • Electrophoresis, Gel, Two-Dimensional / methods
  • Estrogen Antagonists / pharmacology*
  • Flavanones / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase Kinase 5 / genetics
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Peroxiredoxins / genetics
  • Peroxiredoxins / metabolism
  • RNA, Messenger / genetics
  • Reactive Oxygen Species / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Estrogen Antagonists
  • Flavanones
  • Peptide Fragments
  • RNA, Messenger
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • p53 protein (325-355), human
  • PRDX1 protein, human
  • Peroxiredoxins
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP3K5 protein, human
  • naringenin