Format

Send to

Choose Destination
Am J Physiol Gastrointest Liver Physiol. 2014 Jun 1;306(11):G1011-20. doi: 10.1152/ajpgi.00466.2013. Epub 2014 Apr 3.

Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells.

Author information

1
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; and.
2
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
3
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota asaluja@umn.edu.

Abstract

Pancreatic cancer is a devastating disease with a survival rate of <5%. Moreover, pancreatic cancer aggressiveness is closely related to high levels of prosurvival mediators, which can ultimately lead to rapid disease progression. One of the mechanisms that enables tumor cells to evade cellular stress and promote unhindered proliferation is the endoplasmic reticulum (ER) stress response. Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response (UPR). The UPR initially compensates for damage, but it eventually triggers cell death if ER dysfunction is severe or prolonged. Triptolide, a diterpene triepoxide, has been shown to be an effective compound against pancreatic cancer. Our results show that triptolide induces the UPR by activating the PKR-like ER kinase-eukaryotic initiation factor 2α axis and the inositol-requiring enzyme 1α-X-box-binding protein 1 axis of the UPR and leads to chronic ER stress in pancreatic cancer. Our results further show that glucose-regulated protein 78 (GRP78), one of the major regulators of ER stress, is downregulated by triptolide, leading to cell death by apoptosis in MIA PaCa-2 cells and autophagy in S2-VP10 cells.

KEYWORDS:

apoptosis; autophagy; endoplasmic reticulum stress; glucose-regulated protein 78; pancreatic cancer; triptolide

PMID:
24699326
PMCID:
PMC4042112
DOI:
10.1152/ajpgi.00466.2013
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center