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Cell Death Dis. 2019 Feb 22;10(3):187. doi: 10.1038/s41419-019-1360-4.

Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis.

Author information

1
Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, 16499, Korea.
2
Department of Biochemistry and Molecular Biology, Ajou University, Suwon, 16499, Korea.
3
Department of Pharmacy, Ajou University, Suwon, 16499, Korea.
4
Department of Pharmacy, Dankook University, Cheonan, 16890, Korea.
5
Chemical Data-Driven Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea.
6
Asan Institute for Life Sciences, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
7
Center for Advancing Cancer Therapeutics, Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
8
Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, 16499, Korea. kschoi@ajou.ac.kr.
9
Department of Biochemistry and Molecular Biology, Ajou University, Suwon, 16499, Korea. kschoi@ajou.ac.kr.

Abstract

Gambogic acid (GA), a xanthonoid extracted from the resin of the tree, Garcinia hanburyi, was recently shown to exert anticancer activity in multiple studies, but the underlying action mechanism remains unclear. Here, we show that GA induces cancer cell death accompanied by vacuolation in vitro and in vivo. This GA-induced vacuolation in various cancer cells was derived from dilation of the endoplasmic reticulum (ER) and mitochondria, and was blocked by cycloheximide. These findings suggest that GA kills cancer cells by inducing paraptosis, a vacuolization-associated cell death. We found that megamitochondria formation, which arose from the fusion of swollen mitochondria, preceded the fusion of ER-derived vacuoles. GA-induced proteasomal inhibition was found to contribute to the ER dilation and ER stress seen in treated cancer cells, and megamitochondria formation was followed by mitochondrial membrane depolarization. Interestingly, GA-induced paraptosis was effectively blocked by various thiol-containing antioxidants, and this effect was independent of ROS generation. We observed that GA can react with cysteinyl thiol to form Michael adducts, suggesting that the ability of GA to covalently modify the nucleophilic cysteinyl groups of proteins may cause protein misfolding and subsequent accumulation of misfolded proteins within the ER and mitochondria. Collectively, our findings show that disruption of thiol proteostasis and subsequent paraptosis may critically contribute to the anti-cancer effects of GA.

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