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Biochem Biophys Res Commun. 2018 Nov 17;506(1):33-40. doi: 10.1016/j.bbrc.2018.10.047. Epub 2018 Oct 15.

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

Author information

1
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon, 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon, 34113, Republic of Korea.
2
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon, 34141, Republic of Korea.
3
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon, 34141, Republic of Korea; Department of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju, 28644, Republic of Korea.
4
Hematology and Oncology Sections, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
5
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon, 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon, 34113, Republic of Korea. Electronic address: ipchoi@kribb.re.kr.
6
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon, 34141, Republic of Korea. Electronic address: haiyoung@kribb.re.kr.

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.

KEYWORDS:

AML; Fludarabine; NF-κB; TLR4; TXNIP

PMID:
30336978
DOI:
10.1016/j.bbrc.2018.10.047

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