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PMID: 22538852 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Blood ·Vol. 119 ·No. 24 ·2012-06-14 ·Pages 5772-81

Mimura N, Fulciniti M, Gorgun G, Tai YT, 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 NL, Malyankar UM, Hokenson M, Pham T, Zeng Q, Patterson JB, Richardson PG, Munshi NC, Anderson KC

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.

MeSH Terms
Animals Antineoplastic Combined Chemotherapy Protocols/pharmacology,therapeutic use Benzoquinones/pharmacology Bone Marrow Cells/cytology,drug effects,metabolism Boronic Acids/pharmacology,therapeutic use Bortezomib Cell Death/drug effects Cell Line, Tumor Cell Proliferation/drug effects DNA-Binding Proteins/genetics Endoplasmic Reticulum Stress/drug effects Endoribonucleases/antagonists & inhibitors,metabolism Enzyme Activation/drug effects Enzyme Inhibitors/chemistry,pharmacology,therapeutic use Humans Interleukin-6/pharmacology Lactams, Macrocyclic/pharmacology Mice Multiple Myeloma/drug therapy,genetics,pathology Protein Serine-Threonine Kinases/antagonists & inhibitors,metabolism Pyrazines/pharmacology,therapeutic use RNA Splicing/drug effects,genetics RNA, Messenger/genetics,metabolism Regulatory Factor X Transcription Factors Signal Transduction/drug effects Stromal Cells/cytology,drug effects,metabolism Transcription Factors/genetics Unfolded Protein Response/drug effects X-Box Binding Protein 1 eIF-2 Kinase/metabolism
Chemicals
Benzoquinones Boronic Acids DNA-Binding Proteins Enzyme Inhibitors Interleukin-6 Lactams, Macrocyclic Pyrazines RNA, Messenger Regulatory Factor X Transcription Factors Transcription Factors X-Box Binding Protein 1 XBP1 protein, human Xbp1 protein, mouse tanespimycin Bortezomib ERN1 protein, human PERK kinase Protein Serine-Threonine Kinases eIF-2 Kinase Endoribonucleases
Authors & Affiliations
25 authors, click to expand affiliations / ORCID
Mimura Naoya
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Fulciniti Mariateresa
Gorgun Gullu
Tai Yu-Tzu
Cirstea Diana
Santo Loredana
Hu Yiguo
Fabre Claire
Minami Jiro
Ohguchi Hiroto
Kiziltepe Tanyel
Ikeda Hiroshi
Kawano Yutaka
French Maureen
Blumenthal Martina
Tam Victor
Kertesz Nathalie L
Malyankar Uriel M
Hokenson Mark
Pham Tuan
Zeng Qingping
Patterson John B
Richardson Paul G
Munshi Nikhil C
Anderson Kenneth C
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2011-07-366633
Published
2012-06-14
Epub
2012-00-26
Pages
5772-81
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC3382937
Subset
IM
Grants
NCI NIH HHS · P01-CA078378 · United States
NCI NIH HHS · R01CA050947 · United States
PHS HHS · SPORE-P50100707 · United States
NCI NIH HHS · P01 CA078378 · United States
NCI NIH HHS · R01 CA050947 · United States
NCI NIH HHS · P50 CA100707 · United States
External Links
PubMed source DOI: 10.1182/blood-2011-07-366633 PMC Full Text View journal details
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