Abstract
Endoplasmic reticulum stress from unfolded proteins is associated with the proliferation of pancreatic tumor cells, making the many regulatory molecules of this pathway appealing targets for therapy. The objective of our study was to assess potential therapeutic efficacy of inhibitors of unfolded protein response (UPR) in pancreatic cancers focusing on IRE1α inhibitors. IRE1α-mediated XBP-1 mRNA splicing encodes a transcription factor that enhances transcription of chaperone proteins in order to reverse UPR. Proliferation assays using a panel of 14 pancreatic cancer cell lines showed a dose- and time-dependent growth inhibition by IRE1α-specific inhibitors (STF-083010, 2-Hydroxy-1-naphthaldehyde, 3-Ethoxy-5,6-dibromosalicylaldehyde, toyocamycin). Growth inhibition was also noted using a clonogenic growth assay in soft agar, as well as a xenograft in vivo model of pancreatic cancer. Cell cycle analysis showed that these IRE1α inhibitors caused growth arrest at either the G1 or G2/M phases (SU8686, MiaPaCa2) and induced apoptosis (Panc0327, Panc0403). Western blot analysis showed cleavage of caspase 3 and PARP, and prominent induction of the apoptotic molecule BIM. In addition, synergistic effects were found between either STF-083010, 2-Hydroxy-1-naphthaldehyde, 3-Ethoxy-5,6-dibromosalicylaldehyde, or toyocamycin and either gemcitabine or bortezomib. Our data suggest that use of an IRE1α inhibitor is a novel therapeutic approach for treatment of pancreatic cancers.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects*
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Blotting, Western
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Boronic Acids / pharmacology
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Bortezomib
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / pharmacology
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Drug Synergism
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Endoribonucleases / antagonists & inhibitors
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Endoribonucleases / metabolism
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Enzyme Inhibitors / pharmacology*
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Gemcitabine
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Mice, Inbred NOD
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Mice, SCID
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Naphthalenes / pharmacology
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Pyrazines / pharmacology
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RNA Interference
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RNA Splicing / drug effects
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Regulatory Factor X Transcription Factors
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Reverse Transcriptase Polymerase Chain Reaction
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Sulfonamides / pharmacology
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Thiophenes / pharmacology
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Toyocamycin / pharmacology
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Unfolded Protein Response / drug effects*
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Unfolded Protein Response / genetics
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X-Box Binding Protein 1
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Xenograft Model Antitumor Assays
Substances
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Boronic Acids
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DNA-Binding Proteins
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Enzyme Inhibitors
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Naphthalenes
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Pyrazines
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Regulatory Factor X Transcription Factors
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STF 083010
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Sulfonamides
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Thiophenes
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Transcription Factors
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X-Box Binding Protein 1
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XBP1 protein, human
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Xbp1 protein, mouse
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Deoxycytidine
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Bortezomib
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2-hydroxy-1-naphthaldehyde
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ERN1 protein, human
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Protein Serine-Threonine Kinases
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Endoribonucleases
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Toyocamycin
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Gemcitabine