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

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.