抄録
The IRE1a-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.
| 元の言語 | English |
|---|---|
| 記事番号 | e79 |
| ジャーナル | Blood Cancer Journal |
| 巻 | 2 |
| 発行部数 | 7 |
| DOI | |
| 出版物ステータス | Published - 2012 7 |
| 外部発表 | Yes |
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ASJC Scopus subject areas
- Oncology
- Hematology
これを引用
Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing. / Ri, M.; Tashiro, E.; Oikawa, D.; Shinjo, S.; Tokuda, M.; Yokouchi, Y.; Narita, T.; Masaki, A.; Ito, A.; Ding, J.; Kusumoto, S.; Ishida, T.; Komatsu, H.; Shiotsu, Y.; Ueda, R.; Iwawaki, T.; Imoto, M.; Iida, S.
：: Blood Cancer Journal, 巻 2, 番号 7, e79, 07.2012.研究成果: Article
}
TY - JOUR
T1 - Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing
AU - Ri, M.
AU - Tashiro, E.
AU - Oikawa, D.
AU - Shinjo, S.
AU - Tokuda, M.
AU - Yokouchi, Y.
AU - Narita, T.
AU - Masaki, A.
AU - Ito, A.
AU - Ding, J.
AU - Kusumoto, S.
AU - Ishida, T.
AU - Komatsu, H.
AU - Shiotsu, Y.
AU - Ueda, R.
AU - Iwawaki, T.
AU - Imoto, M.
AU - Iida, S.
PY - 2012/7
Y1 - 2012/7
N2 - The IRE1a-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.
AB - The IRE1a-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.
KW - Adenosine analog
KW - ER stress
KW - IRE1α
KW - Multiple myeloma
KW - Toyocamycin
KW - XBP1
UR - http://www.scopus.com/inward/record.url?scp=84866001506&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84866001506&partnerID=8YFLogxK
U2 - 10.1038/bcj.2012.26
DO - 10.1038/bcj.2012.26
M3 - Article
C2 - 22852048
AN - SCOPUS:84866001506
VL - 2
JO - Blood Cancer Journal
JF - Blood Cancer Journal
SN - 2044-5385
IS - 7
M1 - e79
ER -