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Huy, Hangsak,Kim, Tae-Don,Kim, Won Sam,Kim, Dong Oh,Byun, Jae-Eun,Kim, Mi Jeong,Park, Young-Jun,Yoon, Suk Ran,Noh, Ji-Yoon,Lee, Jungwoon,Lee, Kyoo-Hyung,Choi, Inpyo,Jung, Haiyoung Elsevier 2018 Biochemical and biophysical research communication Vol.506 No.1
<P><B>Abstract</B></P> <P>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.</P> <P><B>Highlights</B></P> <P> <UL> <LI> THP-1 cells highly express the Toll-like receptor 4 (TLR4). </LI> <LI> THP-1 cells overcome fludarabine (FA)-induced cytotoxicity by LPS treatment. </LI> <LI> TLR4/NF-κB signaling regulates LPS-induced cell survival under FA treatment. </LI> <LI> TXNIP is crucial for FA-induced cytotoxicity and TLR4/NF-κB-mediated FA resistance. </LI> </UL> </P>
Huy, Hangsak,Song, Hae Young,Kim, Mi Jeong,Kim, Won Sam,Kim, Dong Oh,Byun, Jae‐,Eun,Lee, Jungwoon,Park, Young‐,Jun,Kim, Tae‐,Don,Yoon, Suk Ran,Choi, Eun‐,Ji,Lee, Chul‐,Ho John Wiley and Sons Inc. 2018 Aging cell Vol.17 No.6
<P><B>Abstract</B></P><P>Aging is associated with an inevitable and universal loss of cell homeostasis and restricts an organism's lifespan by an increased susceptibility to diseases and tissue degeneration. The glucose uptake associated with producing energy for cell survival is one of the major causes of ROS production under physiological conditions. However, the overall mechanisms by which glucose uptake results in cellular senescence remain mysterious. In this study, we found that TXNIP deficiency accelerated the senescent phenotypes of MEF cells under high glucose condition. TXNIP<SUP>‐/‐</SUP> MEF cells showed greater induced glucose uptake and ROS levels than wild‐type cells, and <I>N</I>‐acetylcysteine (NAC) treatment rescued the cellular senescence of TXNIP<SUP>‐/‐</SUP> MEF cells. Interestingly, TXNIP<SUP>‐/‐</SUP> MEF cells showed continuous activation of AKT during long‐term subculture, and AKT signaling inhibition completely blocked the cellular senescence of TXNIP<SUP>‐/‐</SUP> MEF cells. In addition, we found that TXNIP interacted with AKT via the PH domain of AKT, and their interaction was increased by high glucose or H<SUB>2</SUB>O<SUB>2</SUB> treatment. The inhibition of AKT activity by TXNIP was confirmed using western blotting and an in vitro kinase assay. TXNIP deficiency in type 1 diabetes mice (Akita) efficiently decreased the blood glucose levels and finally increased mouse survival. However, in normal mice, TXNIP deficiency induced metabolic aging of mice and cellular senescence of kidney cells by inducing AKT activity and aging‐associated gene expression. Altogether, these results suggest that TXNIP regulates cellular senescence by inhibiting AKT pathways via a direct interaction under conditions of glucose‐derived metabolic stress.</P>