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

M. Ri, E. Tashiro, D. Oikawa, S. Shinjo, M. Tokuda, Y. Yokouchi, T. Narita, A. Masaki, A. Ito, J. Ding, S. Kusumoto, T. Ishida, H. Komatsu, Y. Shiotsu, R. Ueda, T. Iwawaki, M. Imoto, S. Iida

研究成果: Article

85 引用 (Scopus)

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
2
発行部数7
DOI
出版物ステータスPublished - 2012 7
外部発表Yes

Fingerprint

Toyocamycin
Endoplasmic Reticulum Stress
Cytotoxins
Multiple Myeloma
Messenger RNA
Activating Transcription Factor 6
Tunicamycin
Thapsigargin
Actinobacteria
Deoxyglucose
HeLa Cells
Heterografts
Endoplasmic Reticulum
Phosphotransferases
Phosphorylation
Apoptosis

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

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 2012, 'Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing', Blood Cancer Journal, 巻. 2, 番号 7, e79. https://doi.org/10.1038/bcj.2012.26
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. / Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing. :: Blood Cancer Journal. 2012 ; 巻 2, 番号 7.
@article{ab707b0c1c1e414d889b4d6126d1196e,
title = "Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing",
abstract = "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.",
keywords = "Adenosine analog, ER stress, IRE1α, Multiple myeloma, Toyocamycin, XBP1",
author = "M. Ri and E. Tashiro and D. Oikawa and S. Shinjo and M. Tokuda and Y. Yokouchi and T. Narita and A. Masaki and A. Ito and J. Ding and S. Kusumoto and T. Ishida and H. Komatsu and Y. Shiotsu and R. Ueda and T. Iwawaki and M. Imoto and S. Iida",
year = "2012",
month = "7",
doi = "10.1038/bcj.2012.26",
language = "English",
volume = "2",
journal = "Blood Cancer Journal",
issn = "2044-5385",
publisher = "Nature Publishing Group",
number = "7",

}

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 -