Sun Haibo, Lin De-Chen, Guo Xiao, Kharabi Masouleh Behzad, Gery Sigal, Cao Qi, Alkan Serhan, Ikezoe Takayuki, Akiba Chie, Paquette Ronald, Chien Wenwen, Müller-Tidow Carsten, Jing Yang, Agelopoulos Konstantin, Müschen Markus, Koeffler H Phillip
Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
Oncotarget. 2016 Apr 5;7(14):18736-49. doi: 10.18632/oncotarget.7702.
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.
癌细胞的存活依赖于未折叠蛋白反应（UPR）来抵抗内质网（ER）内错误折叠蛋白积累所引发的应激。UPR的关键分支IRE1α-XBP1通路在许多癌症中被激活。在此，我们表明XBP1的成熟形式和剪接形式（XBP1s）在急性髓系白血病（AML）细胞系和AML患者样本中的表达均上调。IRE1α核糖核酸酶抑制剂[MKC-3946、2-羟基-1-萘甲醛（HNA）、STF-083010和丰加霉素]阻断XBP1 mRNA剪接，并对AML细胞表现出细胞毒性。IRE1α抑制至少部分通过调节Bcl-2家族蛋白、G1期控制蛋白（p21cip1、p27kip1和细胞周期蛋白D1）以及伴侣蛋白诱导半胱天冬酶依赖性凋亡和G1期细胞周期阻滞。Xbp1缺失的小鼠骨髓细胞对IRE1α抑制剂的生长抑制具有抗性。HNA与硼替佐米或三氧化二砷联合使用在与诱导p-JNK以及降低p-PI3K和p-MAPK相关的AML细胞毒性方面具有协同作用。抑制IRE1α核糖核酸酶活性可增加AML细胞中许多miR的表达，包括miR-34a。抑制miR-34a赋予细胞对HNA的抗性。我们的结果强烈表明，靶向IRE1α驱动的促存活通路是一种用于治疗AML的令人兴奋的治疗方法。
