Oncotarget

Research Papers:

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

Ying Gu _, Mansoureh Barzegar, Xin Chen, Yang Wu, Chaowei Shang, Elahe Mahdavian, Brian A. Salvatore, Shanxiang Jiang and Shile Huang

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Oncotarget. 2015; 6:42322-42333. https://doi.org/10.18632/oncotarget.5996

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Abstract

Ying Gu1,2, Mansoureh Barzegar2, Xin Chen1,2, Yang Wu2, Chaowei Shang2,3, Elahe Mahdavian4, Brian A. Salvatore4, Shanxiang Jiang1, Shile Huang2,3

1Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, P. R. China

2Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

3Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA

4Department of Chemistry and Physics, Louisiana State University, Shreveport, LA, USA

Correspondence to:

Shanxiang Jiang, e-mail: [email protected]

Shile Huang, e-mail: [email protected]

Keywords: fusarochromanone, cell death, reactive oxygen species, JNK, protein phosphatase 2A

Received: August 14, 2015     Accepted: October 05, 2015     Published: October 17, 2015

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.


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