Journal
BIOCHEMICAL PHARMACOLOGY
Volume 128, Issue -, Pages 12-25Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2016.12.022
Keywords
Honokiol; AMLI-ETO; UbcH8
Categories
Funding
- National Natural Science Foundation of China [81501809, 81672087]
- key construction academic subject (traditional Chinese medicine) of Zhejiang Province [2012-XK-A28]
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AMLI-ETO is the most common oncoprotein leading to acute myeloid leukemia (AML), in which 5-year survival rate is only about 30%. However, currently there are no specific therapies for AML patients with AML1-ETO. Here, we report that AMLI-ETO protein is rapidly degraded by Honokiol (HNK), a natural phenolic compound isolated from the plant Magnolia officinalis. HNK induced the degradation of AML1-ETO in a concentration-and time-dependent manner in leukemic cell lines and primary AML blasts with t (8;21) translocation. Mechanistically, HNK obviously increased the expression of UbcH8, an E2-conjugase for the degradation of AMLI-ETO, through triggering accumulation of acetylated histones in the promoter region of UbcH8. Knockdown of UbcH8 by small hairpin RNAs (shRNAs) prevented HNK-induced degradation of AML-ETO, suggesting that UbcH8 plays a critical role in the degradation of AMLI-ETO. HNK inhibited cell proliferation and induced apoptotic death without activation of caspase-3, which was reported to cleave and degrade AMLI-ETO protein. Thus, HNK-induced degradation of AML1-ETO is independent of activation of caspase-3. Finally, HNK reduced the angiogenesis and migration in Kasumi-1-injected zebrafish, decreased xenograft tumor size in a xenograft leukemia mouse model, and prolonged the survival time in mouse C1498 AML model. Collectively, HNK might be a potential treatment for t(8;21) leukemia by targeting AMLI-ETO oncoprotein. (C) 2016 Elsevier Inc. All rights reserved.
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