期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 306, 期 11, 页码 G1011-G1020出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00466.2013
关键词
endoplasmic reticulum stress; apoptosis; autophagy; pancreatic cancer; triptolide; glucose-regulated protein 78
资金
- University of Alabama Birmingham/University of Minnesota National Cancer Institute (NCI) Specialized Program of Research Excellence in Pancreatic Cancer Grant [P50 CA-101955]
- NCI [R01 CA-170946, CA-124723, T32 CA-132715]
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 2 alpha axis and the inositol-requiring enzyme 1 alpha-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.
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