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Exp Cell Res. 2015 Jan 15;330(2):412-22. doi: 10.1016/j.yexcr.2014.08.014. Epub 2014 Aug 17.

Celastrol induces unfolded protein response-dependent cell death in head and neck cancer.

Author information

  • 1Carmen and Ann Adams Department of Pediatrics, Children׳s Hospital of Michigan, Detroit, MI 48201, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA; Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: afribley@med.wayne.edu.
  • 2Carmen and Ann Adams Department of Pediatrics, Children׳s Hospital of Michigan, Detroit, MI 48201, USA; Wayne State University School of Medicine, Detroit, MI, USA.
  • 3Carmen and Ann Adams Department of Pediatrics, Children׳s Hospital of Michigan, Detroit, MI 48201, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
  • 4Carmen and Ann Adams Department of Pediatrics, Children׳s Hospital of Michigan, Detroit, MI 48201, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA; Wayne State University School of Medicine, Detroit, MI, USA.
  • 5The Undergraduate Research Opportunities Program, University of Michigan, Ann Arbor, MI 48109, USA.
  • 6Wayne State University School of Medicine, Detroit, MI, USA.
  • 7Degenerative Disease Research Center, Sanford|Burnham Medical Research Institute La Jolla, CA 92037, USA.

Abstract

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/eIF2α/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.

Copyright © 2014. Published by Elsevier Inc.

KEYWORDS:

Apoptosis; Celastrol; Chaperone; Drug discovery; ER stress; Oral cancer; Protein folding; Unfolded protein response

PMID:
25139619
[PubMed - indexed for MEDLINE]
PMCID:
PMC4280347
Free PMC Article
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