Selective Inhibition Of Unfolded Protein Response Induces Apoptosis In Pancreatic Cancer Cells

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Endoplasmic reticulum (ER) stress is associated with the proliferation of pancreatic tumor cells resulting from unfolded proteins. The unfolded protein response (UPR) is a signaling pathway activated to protect, restore, and aid cells in coping with ER stress. The direct correlation between pancreatic tumor cells and elevated UPR makes the many regulatory molecules of the pathway (e.g. IRE-1) critical targets for therapeutic approaches. The objective of our study was to assess potential therapeutic efficacy of inhibitors of UPR in pancreatic cancers and investigate the mechanisms underlying IRE-1 inhibitor-mediated pancreatic cancer apoptosis. Fourteen pancreatic cancer cell lines and one normal pancreatic epithelial cell line were studied. STF-083010 is a specific inhibitor of IRE-1, which is required for the splicing of XBP-1 mRNA. Spliced XBP-1 mRNA codes for a transcription factor that enhances transcription of chaperone proteins which reverse UPR. MTT assays showed a dose- and time-dependent growth inhibition of 8 pancreatic cancer cell lines by STF-083010, with IC50s ranging between 200 nM to 10 uM. Growth inhibition was also noted using a clonogenic growth assay in soft agar. Annexin V and cell cycle analysis showed that STF-083010 caused growth arrest at the G1 phase in 4 cell lines and induced cell apoptosis in 4 cell lines. Western blot analysis showed cleavage of caspase 3 and PARP, and the induction of the apoptotic molecule Bax. In addition, synergistic effects were found between STF-083010 and either gemcitabine or bortezomib. Our data suggest that an IRE-1 inhibitor is a novel therapeutic approach for treatment of pancreatic cancers. Citation Format: Wenwen Chien, Qiaoyang Sun, Su Lin Lim, Ana D S M Varela, Haibo Sun, Sigal Gery, H Phillip Koeffler. Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4042. doi:10.1158/1538-7445.AM2013-4042