Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells.
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.
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; and.
Nameeta
N
Mujumdar
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; and.
Sulagna
S
Banerjee
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; and.
Zhiyu
Z
Chen
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; and.
Veena
V
Sangwan
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; and.
Rohit
R
Chugh
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; and.
Vikas
V
Dudeja
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Masato
M
Yamamoto
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Selwyn M
SM
Vickers
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.
Ashok K
AK
Saluja
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004852:Epoxy Compounds / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010616:Phenanthrenes / Q000494:pharmacology*; D000071701:Regulatory Factor X Transcription Factors; D013312:Stress, Physiological / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D004268:DNA-Binding Proteins; D004224:Diterpenes; D000091342:Endoplasmic Reticulum Chaperone BiP; D004852:Epoxy Compounds; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D010616:Phenanthrenes; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C001899:triptolide
apoptosis; autophagy; endoplasmic reticulum stress; glucose-regulated protein 78; pancreatic cancer; triptolide