title: Fusarochromanone-induced reactive oxygen species results in activation of JNK cascade and cell death by inhibiting protein phosphatases 2A and 5.
abstract: 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.
authors.affiliation: Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, P. R. China.|Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Barzegar
authors.affiliation: Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, P. R. China.|Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.|Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
authors.forename: Chaowei
authors.initials: C
authors.lastname: Shang
authors.affiliation: Department of Chemistry and Physics, Louisiana State University, Shreveport, LA, USA.
authors.forename: Elahe
authors.initials: E
authors.lastname: Mahdavian
authors.affiliation: Department of Chemistry and Physics, Louisiana State University, Shreveport, LA, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Salvatore
authors.affiliation: Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, P. R. China.
authors.forename: Shanxiang
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.|Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
authors.forename: Shile
authors.initials: S
authors.lastname: Huang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D019556:COS Cells; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D002867:Chromones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000873:Anthracenes; D002867:Chromones; D016166:Free Radical Scavengers; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C089641:protein phosphatase 5; C054523:fusarochromanone; D000111:Acetylcysteine
keywords: JNK; cell death; fusarochromanone; protein phosphatase 2A; reactive oxygen species