Ophiobolin A kills human glioblastoma cells by inducing endoplasmic reticulum stress via disruption of thiol proteostasis
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In Young Kim1,2,*, MiRi Kwon1,2,*, Min-Koo Choi3, Dongjoo Lee4, Dong Min Lee1,2, Min Ji Seo1,2 and Kyeong Sook Choi1,2
1Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea
2BK21 Plus Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea
3College of Pharmacy, Dankook University, Cheonan, Korea
4College of Pharmacy, Ajou University, Suwon, Korea
*These authors contributed equally to this work
Kyeong Sook Choi, email: [email protected]
Keywords: ophiobolin A; endoplasmic reticulum stress; proteostasis; thiol; paraptosis-like cell death
Received: August 05, 2017 Accepted: October 28, 2017 Published: November 20, 2017
Ophiobolin A (OP-A), a fungal sesterterpene from Bipolaris oryzae, was recently shown to have anti-glioma activity. We show here that OP-A induces paraptosis-like cell death accompanied by dilation of the endoplasmic reticulum (ER) in glioma cells, and that CHOP-mediated ER stress plays a critical role in this process. OP-A-induced ER-derived dilation and cell death were found to be independent of reactive oxygen species, but were effectively blocked by various thiol antioxidants. We observed that OP-A can react with cysteinyl thiols to form Michael adducts, suggesting that the ability of OP-A to covalently modify free sulfhydryl groups on proteins may cause protein misfolding and the accumulation of misfolded proteins, leading to paraptosis-like cell death. Taken together, these results indicate that the disruption of thiol proteostasis may critically contribute to the anti-glioma activity of OP-A.
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