TLR4/NF-κB axis induces fludarabine resistance by suppressing TXNIP expression in acute myeloid leukemia cells.

Abstract

Overcoming drug resistance is one of key issues in treating refractory acute myeloid leukemia (AML). The Toll-like receptor 4 (TLR4) signaling pathway is involved in many aspects of biological functions of AML cells, including the regulation of pro-inflammatory cytokine products, myeloid differentiation, and survival of AML cells. Thus, targeting TLR4 of AML patients for therapeutic purposes should be carefully addressed. In this regard, we investigated the possible role of TLR4 as a regulatory factor against fludarabine (FA) cytotoxicity activity. Here, we identified the differential expression of TLR4 and CD14 receptors in AML cell lines and examined their relationship to FA sensitivity. We found that the stimulation of TLR4 with lipopolysaccharide (LPS) in a TLR4-expressing cell line, THP-1, increased cell viability under FA treatment condition and showed that TLR4 stimulation overcame FA sensitivity through the activation of NF-κB, which subsequently upregulated several anti-apoptotic genes. The inhibition of TLR4/NF-κB signaling could partially or completely reverse LPS-induced cell survival under FA treatment conditions. Interestingly, we found that the expression of thioredoxin-interacting protein (TXNIP), a well-known tumor suppressor, was induced by FA treatment; however, it was suppressed by LPS treatment. Furthermore, the expression level of TXNIP was critical for FA-induced cytotoxicity or LPS-induced FA resistance of THP-1 cells. Our data suggest that TXNIP plays an important role in FA-induced cytotoxicity and TLR4/NF-κB-mediated FA resistance of AML cells. Therefore, TXNIP may be a potential therapeutic target for AML treatment.

• Authors: Hangsak Huy, Tae-Don Kim, Won Sam Kim, Dong Oh Kim, Jae-Eun Byun, Mi Jeong Kim, Young-Jun Park, Suk Ran Yoon, Ji-Yoon Noh, Jungwoon Lee, Kyoo-Hyung Lee, Inpyo Choi, Haiyoung Jung
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 506 Issue 1 Pg. 33-40 (11 17 2018) ISSN: 1090-2104 [Electronic] United States
• PMID: 30336978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Carrier Proteins
• Lipopolysaccharide Receptors
• Lipopolysaccharides
• NF-kappa B
• TLR4 protein, human
• TXNIP protein, human
• Toll-Like Receptor 4
• Vidarabine
• fludarabine

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carrier Proteins (genetics, immunology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Regulation, Leukemic
• HL-60 Cells
• Humans
• Lipopolysaccharide Receptors (genetics, immunology)
• Lipopolysaccharides (pharmacology)
• NF-kappa B (genetics, immunology)
• Signal Transduction
• THP-1 Cells
• Toll-Like Receptor 4 (genetics, immunology)
• Vidarabine (analogs & derivatives, pharmacology)