BACKGROUNDImmune escape is a key factor influencing survival rate of lung adenocarcinoma (LUAD) patients, but molecular mechanism of ubiquitin binding enzyme E2T (UBE2T) affecting immune escape of LUAD remains unclear. The objective was to probe role of UBE2T in LUAD.METHODSBioinformatics means were adopted for analyzing UBE2T and forkhead box A1 (FOXA1) expression in LUAD tissues, the gene binding sites, the pathway UBE2T regulates, and the correlation between UBE2T and glycolysis genes. Dual luciferase and chromatin immunoprecipitation (ChIP) assays were conducted for validating the binding relationship between the two genes. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot were employed to evaluate UBE2T, FOXA1, and programmed death ligand 1 (PD-L1) levels in cancer cells. MTT assay was conducted for detecting cell viability. Cytotoxicity assay detected CD8+T cell toxicity. Cytokine expression was assayed by enzyme linked immunosorbent assay (ELISA). Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were assayed by extracellular flow analyzer. Glycolytic gene expression was analyzed by qRT-PCR, and glycolysis-related indicators were detected by ELISA. Immunohistochemistry (IHC) detected CD8+T cell infiltration in tumor tissues.RESULTSFOXA1 and UBE2T were up-regulated in LUAD, and a binding site existed between UBE2T and FOXA1. Overexpressing UBE2T could increase PD-L1 expression and inhibit toxicity of CD8+T cells to LUAD cells. Overexpressing UBE2T repressed CD8+T cell activity in LUAD by activating the glycolysis pathway, and the addition of glycolysis inhibitor 2-deoxy-d-glucose (2-DG) reversed the above results. Mechanistically, FOXA1 promoted the immune escape of LUAD by up-regulating UBE2T and thus mediating glycolysis. In vivo experiments revealed that UBE2T knockdown hindered tumor growth, inhibited PD-L1 expression, and facilitated CD8+T cell infiltration.CONCLUSIONFOXA1 up-regulated the expression of UBE2T, which activated glycolysis, and thus inhibited activity of CD8+T cells, causing immune escape of LUAD.

2024-04-01·International Immunopharmacology

FOXA1-Driven pathways exacerbate Radiotherapy-Induced kidney injury in colorectal cancer

Article

作者: Liang, Guodong ; Zhang, Yuling ; Yu, Tao ; Yuan, Huiqiong ; Wu, Yanni ; Wang, Jingfeng ; Zhang, Minhai ; Yang, Jingyuan ; Li, Li

OBJECTIVEThis study aimed to investigate the role of FOXA1 in acute kidney injury (AKI) induced by radiotherapy in colorectal cancer. Although FOXA1 is known to be aberrantly expressed in malignant tumors, its contribution to AKI remains unclear. This study aimed to explore the involvement of FOXA1 in AKI induced by radiotherapy in colorectal cancer and its influence on the regulation of downstream target genes.METHODSFirstly, a transcriptome analysis was performed on mice to establish a radiation-induced AKI model, and qPCR was used to determine the expression of FOXA1 in renal cell injury models induced by X-ray irradiation. Additionally, FOXA1 was silenced using lentiviral vectors to investigate its effects on the apoptosis of mice with radiation-induced AKI and HK-2 cells. Next, bioinformatics analysis and various experimental validation methods such as ChIP assays, co-immunoprecipitation, and dual-luciferase reporter assays were employed to explore the relationship between FOXA1 and the downstream regulatory factors ITCH promoter and the ubiquitin ligase-degradable TXNIP. Finally, lentiviral overexpression or knockout techniques were used to investigate the impact of the FOXA1/ITCH/TXNIP axis on oxidative stress and the activation of inflammatory body NLRP3.RESULTSThis study revealed that FOXA1 was significantly upregulated in the renal tissues of mice with radiation-induced AKI and in the injured HK-2 cells. Furthermore, in vitro cell experiments and animal experiments demonstrated that FOXA1 suppressed the transcription of the E3 ubiquitin ligase ITCH, thereby promoting apoptosis of renal tubular cells and causing renal tissue damage. Further in vivo animal experiments confirmed that TXNIP, a protein degraded by ITCH ubiquitination, could inhibit oxidative stress and the activation of NLRP3 inflammasome in the AKI mouse model.CONCLUSIONFOXA1 enhances oxidative stress, cell apoptosis, and NLRP3 inflammasome activation by regulating the ITCH/TXNIP axis, thereby exacerbating radiotherapy-induced AKI.

2024-04-01·Chemistry & Biodiversity

Synthesis of Novel Acetyl‐11‐keto‐β‐boswellic Acid Derivatives as Potential Anti‐GBM Agents

Article

作者: Sun, Mingxia ; Zhang, Sen ; Du, Guanhua ; Wang, Jinhua ; Ji, Tengfei

AbstractAcetyl‐11‐keto‐β‐boswellic acid (AKBA) is known to inhibit the growth of glioblastoma (GBM) cells and subcutaneous GBM. A series of acetyl‐11‐keto‐β‐boswellic acid (AKBA) derivatives containing the oxime‐ester functionality or amide side chains were synthesized, and their anti‐GBM activities were evaluated. Some of these compounds exhibited significant inhibitory activity against cell proliferation in U87 and U251 GBM cell lines, with IC50 values in the micromolar concentration range. Cellular thermal shift analysis showed that A‐01 and A‐10 improved the thermal stability of FOXM1, indicating that these highly active compounds may directly bind to FOXM1 in cells. Docking studies of the two most active compounds, A‐01 and A‐10, revealed key interactions between these compounds and the active site of FOXM1, in which the amide moiety at the C‐24 position was essential for improving the activity. These results suggested that A‐10 is a suitable lead molecule for the development of FOXM1 inhibitors. Thus, the rational design of AKBA derivatives with amide side chains holds significant potential for discovering of a new class of triterpenoids capable of inhibiting GBM cell proliferation.

100 项与 FOXA1 inhibitors (Curve Therapeutics) 相关的药物交易

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