期刊
EXPERIMENTAL CELL RESEARCH
卷 330, 期 2, 页码 412-422出版社
ELSEVIER INC
DOI: 10.1016/j.yexcr.2014.08.014
关键词
Celastrol; ER stress; Unfolded protein response; Oral cancer; Apoptosis; Drug discovery; Chaperone; Protein folding
资金
- Wayne State University Fund for Medical Research
- Children's Research Foundation of Michigan
- [DK088227]
- [HL057346]
- [DK0422394]
- [DE019678]
The survival rate for patients with oral squamous cell carcinoma (OSCC) has not seen marked improvement in recent decades despite enhanced efforts in prevention and the introduction of novel therapies. We have reported that pharmacological exacerbation of the unfolded protein response (UPR) is an effective approach to killing OSCC cells. The UPR is executed via distinct signaling cascades whereby an initial attempt to restore folding homeostasis in the endoplasmic reticulum during stress is complemented by an apoptotic response if the defect cannot be resolved. To identify novel small molecules able to overwhelm the adaptive capacity of the UPR in OSCC cells, we engineered a complementary cell-based assay to screen a broad spectrum of chemical matter. Stably transfected CHO-K1 cells that individually report (luciferase) on the PERK/eIF2 alpha/ATF4/CHOP (apoptotic) or the IRE1/XBP1 (adaptive) UPR pathways, were engineered [1]. The triterpenoids dihydrocelastrol and celastrol were identified as potent inducers of UPR signaling and cell death in a primary screen and confirmed in a panel of OSCC cells and other cancer cell lines. Biochemical and genetic assays using OSCC cells and modified murine embryonic fibroblasts demonstrated that intact PERK-eIF2-ATF4-CHOP signaling is required for pro-apoptotic UPR and OSCC death following celastrol treatment. (C) 2014 Published by Elsevier Inc.
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