OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma

Abstract

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a type of malignant tumor with a five-year survival rate of less than 10%. Gemcitabine (GEM) is the most commonly used drug for PDAC chemotherapy. However, a vast majority of patients with PDAC develop resistance after GEM treatment.MethodsWe screened for GEM resistance genes through bioinformatics analysis. We used immunohistochemistry to analyze 3-oxoacid CoA-transferase 1 (OXCT1) expression in PDAC tissues. The survival data were analyzed using the Kaplan–Meier curve. The expression levels of the genes related to OXCT1 and the NF-κB signaling pathway were quantified using real−time quantitative PCR and western blot analyses. We performed flow cytometry to detect the apoptosis rate. Colony formation assay was performed to measure the cell proliferation levels. The cytotoxicity assays of cells were conducted using RTCA. The downstream pathway of OXCT1 was identified via the Gene Set Enrichment Analysis. Tumor growth response to GEM in vivo was also determined in mouse models.ResultsBioinformatics analysis revealed that OXCT1 is the key gene leading to GEM resistance. Patients with high OXCT1 expression exhibited short relapse-free survival under GEM treatment. OXCT1 overexpression in PDAC cell lines exerted inhibitory effect on apoptosis after GEM treatment. However, the down-regulation of OXCT1 showed the opposite effect. Blocking the NF-κB signaling pathway also reduced GEM resistance of PDAC cells. Tumor growth inhibition induced by GEM in vivo reduced after OXCT1 overexpression. Moreover, the effect of OXCT1 on GEM refractoriness in PDAC cell lines was reversed through using an NF-κB inhibitor.ConclusionOXCT1 promoted GEM resistance in PDAC via the NF-κB signaling pathway both in vivo and in vitro. Our results suggest that OXCT1 could be used as a potential therapeutic target for patients with PDAC.

ACAT2 may be a novel predictive biomarker and therapeutic target in lung adenocarcinoma

“…18 Compared with the low OXCT1 expression group, the patients' relapse-free survival (RFS) was substantially shorter in high OXCT1 expression group. 19 DLAT highly expressed in HCC specimens, and high DLAT expression was associated with poor prognosis. 20 We use several online tools to discuss the ACAT2 expression in LUAD, and expression of ACAT2 is associated with prognosis.…”

“…OXCT1, an important rate‐limited enzyme, was involved in the metabolism of ketone body and the production of ATP 18 . Compared with the low OXCT1 expression group, the patients’ relapse‐free survival (RFS) was substantially shorter in high OXCT1 expression group 19 . DLAT highly expressed in HCC specimens, and high DLAT expression was associated with poor prognosis 20…”

TGM2, HMGA2, FXYD3, and LGALS4 genes as biomarkers in acquired oxaliplatin resistance of human colorectal cancer: A systems biology approach

“…AHNAK serves as a p53 cofactor among the top down-regulated hub genes [ 99 ] and its overexpression decreases chemoresistance in breast and lung cancer [ 100 ]. Conflicting results are reported throughout the literature regarding the expression of some of uncommon hub genes such as OXCT1 [ 101 , 102 ], AGR2 [ 103 , 104 ], MUC1 [ 105 , 106 ], GRP78 [ 107 , 108 ], and TRIM54 [ 83 ] in drug-resistant cancer cells. The aforementioned results confirm the hypothesis that resistance index affects gene expression and common hub genes which were independent of OX-RI values exhibit more reliable results.…”

Knockdown of TANK-Binding Kinase 1 Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular-Targeted Drugs

“…NF-κB and its related signaling pathways not only play an important role in the body’s immune response and physiological mechanisms such as inflammation but also promote the occurrence and progression of various malignant tumors ( Yang et al, 2019 ; Jiang et al, 2021a ; Zhou Q et al, 2021 ). In addition, NF-κB can also induce the resistance of malignant tumor cells to anti-tumor drugs ( Ding et al, 2021 ; Kumar et al, 2021 ; Shen et al, 2021 ; Smith and Burger, 2021 ). To this end, the present study intends to systematically investigate the molecular mechanism by which TBK1 regulates the resistance of HCC cells to molecular-targeted drugs.…”