Isochaihulactone-induced DDIT3 causes ER stress-PERK independent apoptosis in glioblastoma multiforme cells
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Sheng-Feng Tsai1, Michael Tao2, Li-Ing Ho3, Tzyy-Wen Chiou4, Shinn-Zong Lin5, Hong-Lin Su1, Horng-Jyh Harn6,7
1Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan
2Department of Bioengineering, University of California, San Diego, La Jolla, California, USA
3Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, School of Medicine, National Yang-Ming University, Taipei, Taiwan
4Department of Life Science, Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan
5Bioinnovation Center, Tzu Chi foundation, Department of Neurosurgery, Hualien Tzu Chi Hospital, Hualien, Taiwan
6Bioinnovation Center, Tzu Chi Foundation, Department of Pathology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
7Department of Pathology, China Medical University Hospital, Taichung, Taiwan
Horng-Jyh Harn, email: [email protected]
Hong-Lin Su, email: [email protected]
Keywords: ER stress, glioblastoma, DDIT3, isochaihulactone, NAG-1
Received: May 11, 2016 Accepted: November 02, 2016 Published: November 10, 2016
The endoplasmic reticulum (ER) is a major site of cellular homeostasis regulation. Under the ER stress condition, Glioblastoma multiform (GBM) cells activate the unfolded protein response. In this study, we discovered isochaihulactone, a natural compound extracted from the Chinese traditional herb Nan-Chai-Hu, which can disrupt ER homeostasis in GBM cell lines. It can induce DNA damage inducible transcript 3 (DDIT3) expression which is independent of 78 kDa glucose-regulated protein (GRP78) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) expression. Flow cytometry results revealed that isochaihulactone trigger the cell cycle arrest at G2/M phase and apoptosis in GBM cells. Isochaihulactone induced DDIT3 led to the expression of NAG-1. The in vivo study showed that isochaihulactone suppressed tumor growth, and DDIT3 and Caspase3 overexpressed in the xenograft model, which is consistent with the in vitro study. Overall, the data revealed that isochaihulactone disrupted ER homeostasis in cancer cells by increasing DDIT3 and NAG-1 expression. Our finding also provides a therapeutic strategy by using isochaihulactone for GBM treatment.
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