Participation of vitamin D-upregulated protein 1 (TXNIP)-ASK1-JNK1 signalosome in the enhancement of AML cell death by a post-cytotoxic differentiation regimen

作     者：Wang, X. Nachliely, M. Harrison, J. S. Danilenko, M. Studzinski, G. P. 

作者机构：Rutgers NJ Med Sch Dept Pathol & Lab Med Newark NJ USA Ben Gurion Univ Negev Dept Clin Biochem & Pharmacol Beer Sheva Israel Univ Connecticut Sch Med Farmington CT USA 

出 版 物：《JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY》 (类固醇生化学与分子生物学杂志)

年 卷 期：2019年第187卷

页      面：166-173页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 1002[医学-临床医学] 07[理学] 

基　　金：National Cancer Institute, NIH [R01CA044722-27] Israel Science Foundation [226/16] US-Israel Binational Science Foundation 

主　　题：Vitamin D Acute myeloid leukemia AraC ASK1 TXNIP Apoptosis Carnosic acid 

摘      要：Standard therapy for Acute Myeloid Leukemia (AML) is rarely curative, and several suggested improvements have had little success so far. We have reported that in an in vitro model of a potential therapeutic regimen for AML, the activity of cytarabine (AraC) is enhanced by a sequential treatment with a combination of the vitamin D2 analog Doxercalciferol (D2) and the plant-derived antioxidant camosic acid (CA). Importantly, the enhancement occurred selectively in patient-derived AML blasts, but not in the normal bone marrow cells. We now demonstrate that TXNIP, previously known as Vitamin D up-regulated protein 1 (VDUP1) [PMID 808674] plays a part in signaling cell death (CD) in this regimen. This is shown by the reduced CD when TXNIP protein levels are decreased by the CRISPR/CAS9 or RNAi technology. Further, we show that direct activation of ASK1 kinase by TXNIP is required for the optimal transmission of the CD signal to apoptotic machinery, regulated by JNK and BIM. These studies provide a rationale for a projected clinical trial of this vitamin D-based new therapeutic regimen for AML.