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

Nameeta Mujumdar, Sulagna Banerjee, Zhiyu Chen, Veena Sangwan, Rohit Chugh, Vikas Dudeja, Masato Yamamoto, Selwyn M. Vickers, Ashok K. Saluja

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)G1011-G1020
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume306
Issue number11
DOIs
StatePublished - Jun 1 2014

Keywords

  • Apoptosis
  • Autophagy
  • Endoplasmic reticulum stress
  • Glucose-regulated protein 78
  • Pancreatic cancer
  • Triptolide

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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