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

被引：346

作者：

Mimura, Naoya ^{[1
]}

Fulciniti, Mariateresa ^{[1
]}

Gorgun, Gullu ^{[1
]}

Tai, Tzu ^{[1
]}

Cirstea, Diana ^{[1
]}

Santo, Loredana ^{[1
]}

Hu, Yiguo ^{[1
]}

Fabre, Claire ^{[1
]}

Ohguchi, Jiro Minami Hiroto ^{[1
]}

Kiziltepe, Tanyel ^{[1
]}

Ikeda, Hiroshi ^{[1
]}

Kawano, Yutaka ^{[1
]}

French, Maureen ^{[1
]}

Blumenthal, Martina ^{[3
]}

Tam, Victor ^{[3
]}

Kertesz, Nathalie L. ^{[3
]}

Malyankar, Uriel M. ^{[3
]}

Hokenson, Mark ^{[3
]}

Pham, Tuan ^{[3
]}

Zeng, Qingping ^{[3
]}

Patterson, John B. ^{[3
]}

Richardson, Paul G. ^{[1
]}

Munshi, Nikhil C. ^{[1
,2
]}

Anderson, Kenneth C. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr,Dept Med Oncol, Boston, MA 02215 USA

[2] Boston Vet Adm Healthcare Syst, W Roxbury, MA USA

[3] MannKind Corp, Valencia, Spain

来源：

BLOOD | 2012年 / 119卷 / 24期

基金：

美国国家卫生研究院;

关键词：

UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; TRANSCRIPTION FACTOR; BONE-MARROW; IN-VITRO; ER STRESS; CELLS; SURVIVAL; PATHWAY; IDENTIFICATION;

D O I：

10.1182/blood-2011-07-366633

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 1 alpha (IRE1 alpha) 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 IRE1 alpha-XBP1 pathway is a potential therapeutic target in MM using a small-molecule IRE1 alpha 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 IRE1 alpha endoribonuclease domain is a potential therapeutic option in MM. (Blood. 2012; 119(24):5772-5781)

引用

页码：5772 / 5781

页数：10

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