Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2017; 8:64651.

Inhibition of IRE1α-driven pro-survival pathways is a promising therapeutic application in acute myeloid leukemia

Haibo Sun _, De-Chen Lin, Xiao Guo, Behzad Kharabi Masouleh, Sigal Gery, Qi Cao, Serhan Alkan, Takayuki Ikezoe, Chie Akiba, Ronald Paquette, Wenwen Chien, Carsten Müller-Tidow, Yang Jing, Konstantin Agelopoulos, Markus Müschen and Phillip H. Koeffler

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Oncotarget. 2016; 7:18736-18749. https://doi.org/10.18632/oncotarget.7702

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Abstract

Haibo Sun1,2,*, De-Chen Lin1,*, Xiao Guo1,*, Behzad Kharabi Masouleh3, Sigal Gery1, Qi Cao1, Serhan Alkan1, Takayuki Ikezoe4, Chie Akiba1, Ronald Paquette5, Wenwen Chien6, Carsten Müller-Tidow7, Yang Jing4, Konstantin Agelopoulos8, Markus Müschen9, H. Phillip Koeffler1,6

1Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

2Department of Surgery, University of California San Francisco, San Francisco, CA, USA

3Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany

4Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi, Japan

5Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

6Cancer Science Institute of Singapore, National University of Singapore, Singapore

7Department of Hematology and Oncology, University Hospital Halle, Halle, Germany

8Department of Medicine, Hematology and Oncology, University of Muenster, Muenster, Germany

9Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA

*These authors have contributed equally to this work

Correspondence to:

Haibo Sun, e-mail: Haibo.Sun@ucsf.edu

De-chen Lin, e-mail: De-chen.Lin@cshs.org

Keywords: IRE1, ER stress, XBP1, unfolded protein response, micro RNA

Received: July 13, 2015     Accepted: January 29, 2016     Published: February 25, 2016

ABSTRACT

Survival of cancer cells relies on the unfolded protein response (UPR) to resist stress triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The IRE1α-XBP1 pathway, a key branch of the UPR, is activated in many cancers. Here, we show that the expression of both mature and spliced forms of XBP1 (XBP1s) is up-regulated in acute myeloid leukemia (AML) cell lines and AML patient samples. IRE1α RNase inhibitors [MKC-3946, 2-hydroxy-1-naphthaldehyde (HNA), STF-083010 and toyocamycin] blocked XBP1 mRNA splicing and exhibited cytotoxicity against AML cells. IRE1α inhibition induced caspase-dependent apoptosis and G1 cell cycle arrest at least partially by regulation of Bcl-2 family proteins, G1 phase controlling proteins (p21cip1, p27kip1 and cyclin D1), as well as chaperone proteins. Xbp1 deleted murine bone marrow cells were resistant to growth inhibition by IRE1α inhibitors. Combination of HNA with either bortezomib or AS2O3 was synergistic in AML cytotoxicity associated with induction of p-JNK and reduction of p-PI3K and p-MAPK. Inhibition of IRE1α RNase activity increased expression of many miRs in AML cells including miR-34a. Inhibition of miR-34a conferred cellular resistance to HNA. Our results strongly suggest that targeting IRE1α driven pro-survival pathways represent an exciting therapeutic approach for the treatment of AML.


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