title: Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells.
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.
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Wenwen
authors: W
authors: Chien
authors: Ling-Wen
authors: LW
authors: Ding
authors: Qiao-Yang
authors: QY
authors: Sun
authors: Lucia A
authors: LA
authors: Torres-Fernandez
authors: Siew Zhuan
authors: SZ
authors: Tan
authors: Jinfen
authors: J
authors: Xiao
authors: Su Lin
authors: SL
authors: Lim
authors: Manoj
authors: M
authors: Garg
authors: Kian Leong
authors: KL
authors: Lee
authors: Shojiro
authors: S
authors: Kitajima
authors: Sumiko
authors: S
authors: Takao
authors: Wei Zhong
authors: WZ
authors: Leong
authors: Haibo
authors: H
authors: Sun
authors: Itay
authors: I
authors: Tokatly
authors: Lorenz
authors: L
authors: Poellinger
authors: Sigal
authors: S
authors: Gery
authors: Phillip H
authors: PH
authors: Koeffler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009281:Naphthalenes / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D012326:RNA Splicing / Q000187:drug effects; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014127:Toyocamycin / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000235:genetics; D000071717:X-Box Binding Protein 1; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D001897:Boronic Acids; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011719:Pyrazines; D000071701:Regulatory Factor X Transcription Factors; C556690:STF 083010; D013449:Sulfonamides; D013876:Thiophenes; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D003841:Deoxycytidine; D000069286:Bortezomib; C062247:2-hydroxy-1-naphthaldehyde; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D014127:Toyocamycin; D000093542:Gemcitabine