Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells

// Wenwen Chien 1,* , Ling-Wen Ding 1,* , Qiao-Yang Sun 1 , Lucia A. Torres-Fernandez 1 , Siew Zhuan Tan 1 , Jinfen Xiao 1 , Su Lin Lim 1 , Manoj Garg 1 , Kian Leong Lee 1 , Shojiro Kitajima 1 , Sumiko Takao 1 , Wei Zhong Leong 1 , Haibo Sun 2 , Itay Tokatly 1,3 , Lorenz Poellinger 1 , Sigal Gery 2 and Phillip H. Koeffler 1,2,4 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore 2 Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California, USA 3 Cancer Research Center, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Israel 4 National University Cancer Institute, Singapore * Co-first authors Correspondence: Wenwen Chien, email: // Keywords : UPR, pancreatic cancer, IRE1α Received : April 15, 2014 Accepted : May 30, 2014 Published : June 1, 2014 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.