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