Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma

Naoya Mimura, Mariateresa Fulciniti, Gullu Gorgun, Yu Tzu Tai, Diana Cirstea, Loredana Santo, Yiguo Hu, Claire Fabre, Jiro Minami, Hiroto Ohguchi, Tanyel Kiziltepe, Hiroshi Ikeda, Yutaka Kawano, Maureen French, Martina Blumenthal, Victor Tam, Nathalie L. Kertesz, Uriel M. Malyankar, Mark Hokenson, Tuan PhamQingping Zeng, John B. Patterson, Paul G. Richardson, Nikhil C. Munshi, Kenneth C. Anderson

Research output: Contribution to journalArticle

225 Scopus citations

Abstract

Multiple myeloma (MM) cells are characterized by high protein synthesis resulting in chronic endoplasmic reticulum (ER) stress, which is adaptively managed by the unfolded protein response. Inositol-requiring enzyme 1α (IRE1α) is activated to splice X-box binding protein 1 (XBP1) mRNA, thereby increasing XBP1s protein, which in turn regulates genes responsible for protein folding and degradation during the unfolded protein response. In this study, we examined whether IRE1α-XBP1 pathway is a potential therapeutic target in MM using a small-molecule IRE1α endoribonuclease domain inhibitor MKC-3946. MKC-3946 triggered modest growth inhibition in MM cell lines, without toxicity in normal mononuclear cells. Importantly, it significantly enhanced cytotoxicity induced by bortezomib or 17-AAG, even in the presence of bone marrow stromal cells or exogenous IL-6. Both bortezomib and 17-AAG induced ER stress, evidenced by induction of XBP1s, which was blocked by MKC-3946. Apoptosis induced by these agents was enhanced by MKC-3946, associated with increased CHOP. Finally, MKC-3946 inhibited XBP1 splicing in a model of ER stress in vivo, associated with significant growth inhibition of MM cells. Taken together, our results demonstrate that blockade of XBP1 splicing by inhibition of IRE1α endoribonuclease domain is a potential therapeutic option in MM.

Original languageEnglish (US)
Pages (from-to)5772-5781
Number of pages10
JournalBlood
Volume119
Issue number24
DOIs
StatePublished - Jun 14 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Mimura, N., Fulciniti, M., Gorgun, G., Tai, Y. T., Cirstea, D., Santo, L., Hu, Y., Fabre, C., Minami, J., Ohguchi, H., Kiziltepe, T., Ikeda, H., Kawano, Y., French, M., Blumenthal, M., Tam, V., Kertesz, N. L., Malyankar, U. M., Hokenson, M., ... Anderson, K. C. (2012). Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma. Blood, 119(24), 5772-5781. https://doi.org/10.1182/blood-2011-07-366633