Fusarochromanone-induced reactive oxygen species results in activation of JNK cascade and cell death by inhibiting protein phosphatases 2A and 5

• DOI: 10.18632/oncotarget.5996
• Publication Date: 2015-10-27T14:16:41Z
• Authors: Ying Gu; Mansoureh Barzegar; Xin Chen; Yang Wu; Chaowei Shang; Elahe Mahdavian; Brian A. Salvatore; Shanxiang Jiang; Shile Huang
• Keywords: Anthracenes; 0301 basic medicine; Cell Death; Dose-Response Relationship, Drug; Cell Survival; MAP Kinase Signaling System; Blotting, Western; JNK Mitogen-Activated Protein Kinases; Nuclear Proteins; Free Radical Scavengers; Acetylcysteine; 3. Good health; Enzyme Activation; 03 medical and health sciences; HEK293 Cells; Chromones; COS Cells; Chlorocebus aethiops; Phosphoprotein Phosphatases; Animals; Humans; Protein Phosphatase 2; Reactive Oxygen Species

Recent studies have shown that fusarochromanone (FC101), a mycotoxin, is cytotoxic in a variety of cell lines. However, the molecular mechanism underlying its cytotoxicity remains elusive. Here we found that FC101 induced cell death in COS7 and HEK293 cells in part by activating JNK pathway. This is evidenced by the findings that inhibition of JNK with SP600125 or expression of dominant negative c-Jun partially prevented FC101-induced cell death. Furthermore, we observed that FC101-activated JNK pathway was attributed to induction of reactive oxygen species (ROS). Pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger and antioxidant, suppressed FC101-induced activation of JNK and cell death. Moreover, we noticed that FC101 inhibited the serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5) in the cells, which was abrogated by NAC. Overexpression of PP2A or PP5 partially prevented FC101-induced activation of JNK and cell death. The results indicate that FC101-induced ROS inhibits PP2A and PP5, leading to activation of JNK pathway and consequently resulting in cell death.