Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing

作者：Masaki Ri, Etsu Tashiro, Daisuke Oikawa, Satoko Shinjo, Mio Tokuda, Yumi Yokouchi, Takuma Narita, A Masaki, Asahi Ito, Jian Ding, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Yukimasa Shiotsu, Ryuzo Ueda, Takao Iwawaki, Masaya Imoto, Shinsuke Iida · 发表于：Blood Cancer Journal · 年份：2012 · DOI：10.1038/bcj.2012.26 · 被引用次数：185 · 研究领域：Endoplasmic Reticulum Stress and Disease、Signaling Pathways in Disease、Ubiquitin and proteasome pathways

The IRE1α-XBP1 pathway, a key component of the endoplasmic reticulum (ER) stress response, is considered to be a critical regulator for survival of multiple myeloma (MM) cells. Therefore, the availability of small-molecule inhibitors targeting this pathway would offer a new chemotherapeutic strategy for MM. Here, we screened small-molecule inhibitors of ER stress-induced XBP1 activation, and identified toyocamycin from a culture broth of an Actinomycete strain. Toyocamycin was shown to suppress thapsigargin-, tunicamycin- and 2-deoxyglucose-induced XBP1 mRNA splicing in HeLa cells without affecting activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) activation. Furthermore, although toyocamycin was unable to inhibit IRE1α phosphorylation, it prevented IRE1α-induced XBP1 mRNA cleavage in vitro. Thus, toyocamycin is an inhibitor of IRE1α-induced XBP1 mRNA cleavage. Toyocamycin inhibited not only ER stress-induced but also constitutive activation of XBP1 expression in MM lines as well as primary samples from patients. It showed synergistic effects with bortezomib, and induced apoptosis of MM cells including bortezomib-resistant cells at nanomolar levels in a dose-dependent manner. It also inhibited growth of xenografts in an in vivo model of human MM. Taken together, our results suggest toyocamycin as a lead compound for developing anti-MM therapy and XBP1 as an appropriate molecular target for anti-MM therapy.