title: Isochaihulactone-induced DDIT3 causes ER stress-PERK independent apoptosis in glioblastoma multiforme cells.
abstract: 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.
authors.affiliation: Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan.
authors.forename: Sheng-Feng
authors.initials: SF
authors.lastname: Tsai
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Tao
authors.affiliation: Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Li-Ing
authors.initials: LI
authors.lastname: Ho
authors.affiliation: Department of Life Science, Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan.
authors.forename: Tzyy-Wen
authors.initials: TW
authors.lastname: Chiou
authors.affiliation: Bioinnovation Center, Tzu Chi foundation, Department of Neurosurgery, Hualien Tzu Chi Hospital, Hualien, Taiwan.
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
authors.affiliation: Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan.
authors.forename: Hong-Lin
authors.initials: HL
authors.lastname: Su
authors.affiliation: Bioinnovation Center, Tzu Chi Foundation, Department of Pathology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.|Department of Pathology, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Horng-Jyh
authors.initials: HJ
authors.lastname: Harn
mesh_terms: D015107:4-Butyrolactone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D052117:Benzodioxoles / Q000008:administration & dosage* / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D055436:Growth Differentiation Factor 15 / Q000378:metabolism; D006801:Humans; D051379:Mice; D051742:Transcription Factor CHOP / Q000378:metabolism*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D052117:Benzodioxoles; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C512868:isochaihulactone; D051742:Transcription Factor CHOP; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; C505407:CASP3 protein, human; D053148:Caspase 3; D015107:4-Butyrolactone
keywords: DDIT3; ER stress; NAG-1; glioblastoma; isochaihulactone