Fumonisin B1 induces autophagic cell death via activation of ERN1-MAPK8/9/10 pathway in monkey kidney MARC-145 cells.
Mycotoxins are secondary fungal metabolites that are capable of inducing a variety of toxic effects in animals and humans resulting from the consumption of the contaminated food. Understanding the mechanisms of the toxicities behind these mycotoxins is required to develop mechanism-based approach to counteract their toxic potential. Fumonisin B1 (FB1) is the most prevalent member of fumonisins that are a group of mycotoxins produced primarily by Fusarium verticillioides and Fusarium proliferatum. Kidney is one of the primary target organs for FB1 action. Using monkey kidney MARC-145 cells as an intro model, we found that FB1 induced caspase-independent programmed cell death accompanied with autophagy induction. Inhibition of autophagy by either chemical inhibitors or RNAi approach led to a significant reduction in cell death by FB1 exposure, indicating possible involvement of autophagy-mediated cell death in nephrotoxicity of FB1. Further mechanistic investigation revealed that activation of ERN1-MAPK8/9/10 axis played a critical role in autophagy induction and autophagy-mediated cell death by FB1 exposure. In addition, we demonstrated that disruption of sphingolipid metabolism was an apical event in FB1-induced ERN1-MAPK8/9/10-mediated autophagic cell death in MARC-145 cells. Lastly, we identified curcumin, a naturally occurring plant phenolic compound, as a possible anti-FB1 agent that can be used to protect kidney cells from FB1-induced cell death through inhibition of MAPK8/9/10 activation.
Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, No 17 Qinghua East Road, Haidian District, Beijing, 100083, China.
Shutao
S
Yin
Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, No 17 Qinghua East Road, Haidian District, Beijing, 100083, China.
Xiao
X
Guo
Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, No 17 Qinghua East Road, Haidian District, Beijing, 100083, China.
Jinghua
J
Li
College of Veterinary Medicine, China Agricultural University, No 2 Yunmingyuan West Road, Hiadian District, Beijing, 1000193, China. flh@cau.edu.cn.
Linghong
L
Fan
Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, No 17 Qinghua East Road, Haidian District, Beijing, 100083, China. hongbo@cau.edu.cn.
Hongbo
H
Hu
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002522:Chlorocebus aethiops; D003474:Curcumin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D037341:Fumonisins / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D037341:Fumonisins; C056933:fumonisin B1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D003474:Curcumin
Autophagic cell death; Autophagy; Curcumin; ERN1; Fumonisin B1; MAPK8/9/10; Nephrotoxicity