Triptolide sensitizes pancreatic cancer cells to TRAIL-induced activation of the death receptor pathway

Zhiyu Chen; Veena Sangwan; Sulagna Banerjee; Rohit Chugh; Vikas Dudeja; Selwyn M Vickers; Ashok K Saluja

doi:10.1016/j.canlet.2014.03.016

Triptolide sensitizes pancreatic cancer cells to TRAIL-induced activation of the death receptor pathway

Cancer Lett. 2014 Jun 28;348(1-2):156-66. doi: 10.1016/j.canlet.2014.03.016. Epub 2014 Mar 21.

Authors

Zhiyu Chen¹, Veena Sangwan², Sulagna Banerjee³, Rohit Chugh⁴, Vikas Dudeja⁵, Selwyn M Vickers⁶, Ashok K Saluja⁷

Affiliations

¹ Department of Surgery, University of Minnesota, Minneapolis, MN 55455, United States; Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China. Electronic address: chenz@umn.edu.
² Department of Surgery, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: sang0001@umn.edu.
³ Department of Surgery, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: sbanerje@umn.edu.
⁴ Department of Surgery, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: chugh012@umn.edu.
⁵ Department of Surgery, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: dudej001@umn.edu.
⁶ Department of Surgery, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: Vickers@umn.edu.
⁷ Department of Surgery, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: asaluja@umn.edu.

Abstract

The tumor necrosis factor related apoptosis-inducing ligand (TRAIL) causes cancer cell death, but many cancers, including pancreatic cancer, are resistant to TRAIL therapy. A combination of TRAIL and the diterpene triepoxide, triptolide, is effective in inducing pancreatic cancer cell death. Triptolide increases levels of death receptor DR5 and decreases the pro-survival FLICE-like inhibitory protein (c-FLIP), which contribute to the activation of caspase-8. This combination further causes both lysosomal and mitochondrial membrane permeabilization, resulting in cell death. Our study provides a mechanism by which triptolide sensitizes TRAIL resistant cells, which may become a novel therapeutic strategy against pancreatic cancer.

Keywords: Apoptosis; Death receptor; Pancreatic cancer; TRAIL; Triptolide.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Alkylating / pharmacology
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects*
BH3 Interacting Domain Death Agonist Protein / metabolism
CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
Caspase 8 / genetics
Caspase 8 / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Diterpenes / pharmacology
Drug Resistance, Neoplasm / drug effects*
Enzyme Activation
Epoxy Compounds / pharmacology
Humans
Lysosomes / drug effects
Lysosomes / metabolism
Mice
Mitochondrial Membranes / drug effects
Mitochondrial Membranes / metabolism
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism*
Pancreatic Neoplasms / pathology
Permeability
Phenanthrenes / pharmacology
RNA Interference
Receptors, TNF-Related Apoptosis-Inducing Ligand / agonists*
Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
Signal Transduction / drug effects*
TNF-Related Apoptosis-Inducing Ligand / pharmacology
Transfection
bcl-2-Associated X Protein / metabolism

Substances

Antineoplastic Agents, Alkylating
BAX protein, human
BH3 Interacting Domain Death Agonist Protein
BID protein, human
CASP8 and FADD-Like Apoptosis Regulating Protein
CFLAR protein, human
Diterpenes
Epoxy Compounds
Phenanthrenes
Receptors, TNF-Related Apoptosis-Inducing Ligand
TNF-Related Apoptosis-Inducing Ligand
TNFRSF10B protein, human
bcl-2-Associated X Protein
triptolide
CASP8 protein, human
Caspase 8

Abstract

Publication types

MeSH terms

Substances

Grants and funding