Inhibition of IRE1?-driven pro-survival pathways is a promising therapeutic application in acute myeloid leukemia.

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 IRE1?-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. IRE1? RNase inhibitors [MKC-3946, 2-hydroxy-1-naphthaldehyde (HNA), STF-083010 and toyocamycin] blocked XBP1 mRNA splicing and exhibited cytotoxicity against AML cells. IRE1? 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 IRE1? 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 IRE1? 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 IRE1? driven pro-survival pathways represent an exciting therapeutic approach for the treatment of AML.

SUBMITTER: Sun H 

PROVIDER: S-EPMC4951325 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature