Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells
| Autor: | Phillip Koeffler, Su Lin Lim, Manoj Garg, Jin-Fen Xiao, Lorenz Poellinger, Shojiro Kitajima, Wenwen Chien, Itay Tokatly, Kian Leong Lee, Haibo Sun, Qiao-Yang Sun, Wei Zhong Leong, Sumiko Takao, Siew Zhuan Tan, Lucia A. Torres-Fernandez, Sigal Gery, Ling-Wen Ding |
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| Předmět: |
X-Box Binding Protein 1
pancreatic cancer Apoptosis UPR Mice SCID Deoxycytidine Bortezomib chemistry.chemical_compound 0302 clinical medicine Mice Inbred NOD Pancreatic tumor Enzyme Inhibitors Toyocamycin Sulfonamides 0303 health sciences Reverse Transcriptase Polymerase Chain Reaction Cell Cycle Drug Synergism Cell cycle Boronic Acids 3. Good health DNA-Binding Proteins Gene Expression Regulation Neoplastic Oncology Pyrazines 030220 oncology & carcinogenesis RNA Interference Growth inhibition Research Paper RNA Splicing Blotting Western Regulatory Factor X Transcription Factors Thiophenes Naphthalenes Protein Serine-Threonine Kinases Biology 03 medical and health sciences Cell Line Tumor Pancreatic cancer Endoribonucleases medicine Animals Humans Clonogenic assay Cell Proliferation 030304 developmental biology Cell growth Endoplasmic reticulum IRE1α medicine.disease Xenograft Model Antitumor Assays Gemcitabine Molecular biology Pancreatic Neoplasms chemistry Unfolded Protein Response Cancer research Unfolded protein response Transcription Factors |
| Zdroj: | Scopus-Elsevier Oncotarget |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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