Identification of Doxorubicin as an Inhibitor of the IRE1α-XBP1 Axis of the Unfolded Protein Response

• DOI: 10.1038/srep33353
• Publication Date: 2016-09-16T11:02:13Z
• Authors: Dadi Jiang; Connor Lynch; Bruno C. Medeiros; Michaela Liedtke; Rakesh Bam; Arvin B. Tam; Zhifen Yang; Muthuraman Alagappan; Parveen Abidi; Quynh-Thu Le; Amato J. Giaccia; Nicholas C. Denko; Maho Niwa; Albert C. Koong
• Keywords: X-Box Binding Protein 1; 0303 health sciences; Cell Death; Topoisomerase Inhibitors; RNA Splicing; Protein Serine-Threonine Kinases; Article; 3. Good health; 03 medical and health sciences; Doxorubicin; Cell Line, Tumor; Endoribonucleases; Unfolded Protein Response; Humans; Etoposide; Signal Transduction

AbstractActivation of the IRE1α-XBP1 branch of the unfolded protein response (UPR) has been implicated in multiple types of human cancers, including multiple myeloma (MM). Through anin silicodrug discovery approach based on protein-compound virtual docking, we identified the anthracycline antibiotic doxorubicin as anin vitroandin vivoinhibitor of XBP1 activation, a previously unknown activity for this widely utilized cancer chemotherapeutic drug. Through a series of mechanistic and phenotypic studies, we showed that this novel activity of doxorubicin was not due to inhibition of topoisomerase II (Topo II). Consistent with its inhibitory activity on the IRE1α-XBP1 branch of the UPR, doxorubicin displayed more potent cytotoxicity against MM cell lines than other cancer cell lines that have lower basal IRE1α-XBP1 activity. In addition, doxorubicin significantly inhibited XBP1 activation in CD138+tumor cells isolated from MM patients. Our findings suggest that the UPR-modulating activity of doxorubicin may be utilized clinically to target IRE1α–XBP1-dependent tumors such as MM.