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

Autor: Wang X; Department of Pathology & Laboratory Medicine, Rutgers NJ Medical School, Newark, NJ, United States., Nachliely M; Department of Clinical Biochemistry & Pharmacology, Ben-Gurion University of the Negev, Beer Sheva, Israel., Harrison JS; University of Connecticut School of Medicine, Farmington, CT, United States., Danilenko M; Department of Clinical Biochemistry & Pharmacology, Ben-Gurion University of the Negev, Beer Sheva, Israel., Studzinski GP; Department of Pathology & Laboratory Medicine, Rutgers NJ Medical School, Newark, NJ, United States. Electronic address: studzins@njms.rutgers.edu.
Jazyk: angličtina
Zdroj: The Journal of steroid biochemistry and molecular biology [J Steroid Biochem Mol Biol] 2019 Mar; Vol. 187, pp. 166-173. Date of Electronic Publication: 2018 Nov 30.
DOI: 10.1016/j.jsbmb.2018.11.015
Abstrakt: 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 carnosic 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.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: