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Ri M, Tashiro E, Oikawa D, et al. Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing. Blood Cancer J. 2012;2(7):e79doi: 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. (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, 2(7), e79. https://doi.org/10.1038/bcj.2012.26
Ri, M, et al. "Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing." Blood cancer journal vol. 2,7 (2012): e79. doi: 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 J. 2012 Jul;2(7):e79. doi: 10.1038/bcj.2012.26. Epub 2012 Jul 20. PMID: 22852048; PMCID: PMC3408640.
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Blood Cancer J. 2012 Jul;2(7):e79. doi: 10.1038/bcj.2012.26. Epub 2012 Jul 20.

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

Blood cancer journal

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

PMID: 22852048 PMCID: PMC3408640 DOI: 10.1038/bcj.2012.26

Abstract

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.

Keywords: ER stress; IRE1α; XBP1; adenosine analog; multiple myeloma; toyocamycin

References

  1. J Am Soc Nephrol. 2003 Apr;14(4):1037-45 - PubMed
  2. Dev Cell. 2003 Feb;4(2):265-71 - PubMed
  3. Mol Cell Biol. 2003 Nov;23(21):7448-59 - PubMed
  4. Biochim Biophys Acta. 1967 Nov 21;149(1):41-9 - PubMed
  5. Cell. 2008 Jan 11;132(1):89-100 - PubMed
  6. Leukemia. 2011 Oct;25(10):1610-9 - PubMed
  7. Mol Cell. 2000 Nov;6(5):1099-108 - PubMed
  8. Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9946-51 - PubMed
  9. Nature. 2009 Feb 5;457(7230):736-40 - PubMed
  10. Cell. 2001 Dec 28;107(7):893-903 - PubMed
  11. Genes Dev. 2000 Nov 1;14(21):2725-36 - PubMed
  12. Blood. 2008 Sep 15;112(6):2177-8 - PubMed
  13. Nature. 2009 Feb 5;457(7230):687-93 - PubMed
  14. Blood. 2010 Jul 15;116(2):250-3 - PubMed
  15. Biochim Biophys Acta. 1969 Mar 18;179(1):50-7 - PubMed
  16. J Biol Chem. 2003 Aug 15;278(33):31024-32 - PubMed
  17. J Antibiot (Tokyo). 1990 Dec;43(12):1586-9 - PubMed
  18. Science. 2007 Nov 9;318(5852):944-9 - PubMed
  19. Mol Cell. 2000 Dec;6(6):1355-64 - PubMed
  20. Haematologica. 2005 Jun;90(6):810-7 - PubMed
  21. Leukemia. 2010 Aug;24(8):1506-12 - PubMed
  22. Biochem Biophys Res Commun. 2006 Nov 24;350(3):709-15 - PubMed
  23. Cell. 2001 Dec 28;107(7):881-91 - PubMed
  24. Blood. 2004 Mar 1;103(5):1799-806 - PubMed
  25. J Antibiot (Tokyo). 1989 Jan;42(1):102-6 - PubMed
  26. J Antibiot (Tokyo). 1956 Mar;9(2):60-2 - PubMed
  27. Leukemia. 2011 Oct;25(10):1533-42 - PubMed
  28. EMBO J. 1996 Jun 17;15(12):3028-39 - PubMed
  29. Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14343-8 - PubMed
  30. Nat Cell Biol. 2000 Jun;2(6):326-32 - PubMed
  31. Bioorg Med Chem. 1997 Jan;5(1):193-203 - PubMed
  32. Dev Cell. 2002 Jul;3(1):99-111 - PubMed
  33. Nature. 2004 Sep 23;431(7007):471-6 - PubMed
  34. J Antibiot (Tokyo). 2007 Sep;60(9):547-53 - PubMed
  35. Cell. 1997 Sep 19;90(6):1031-9 - PubMed
  36. J Hepatol. 2003 May;38(5):605-14 - PubMed
  37. Cancer Cell. 2007 Apr;11(4):349-60 - PubMed
  38. Mol Biol Cell. 2004 Jun;15(6):2537-48 - PubMed
  39. Cancer Res. 2003 Jan 15;63(2):424-31 - PubMed
  40. Leukemia. 2009 Nov;23(11):1964-79 - PubMed
  41. Immunity. 2002 Jul;17(1):51-62 - PubMed
  42. Mol Biol Cell. 1999 Nov;10(11):3787-99 - PubMed
  43. Nature. 1999 Jan 21;397(6716):271-4 - PubMed
  44. Nature. 2001 Jul 19;412(6844):300-7 - PubMed
  45. Cancer Sci. 2008 Nov;99(11):2309-14 - PubMed
  46. Biochem Biophys Res Commun. 2008 Jan 25;365(4):777-83 - PubMed
  47. Blood. 2011 Jan 27;117(4):1311-4 - PubMed
  48. J Antibiot (Tokyo). 2008 May;61(5):303-11 - PubMed
  49. Science. 2003 Nov 28;302(5650):1533-7 - PubMed
  50. Cancer Chemother Rep. 1968 Feb;52(2):301-3 - PubMed
  51. Genes Dev. 2002 Feb 15;16(4):452-66 - PubMed

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