OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma
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 scre...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:948f63ba82084a768da6ea5f421b1b8d2021-11-05T08:58:19ZOXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma2234-943X10.3389/fonc.2021.698302https://doaj.org/article/948f63ba82084a768da6ea5f421b1b8d2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.698302/fullhttps://doaj.org/toc/2234-943XBackgroundPancreatic 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.Jinsheng DingJinsheng DingJinsheng DingHui LiHui LiYang LiuYang LiuYongjie XieYongjie XieJie YuHuizhi SunHuizhi SunDi XiaoYizhang ZhouLi BaoHongwei WangChuntao GaoFrontiers Media S.A.articlePancreatic ductal adenocarcinomaOXCT1gemcitabinechemoresistanceNF-κBNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021) |
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DOAJ |
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| topic |
Pancreatic ductal adenocarcinoma OXCT1 gemcitabine chemoresistance NF-κB Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
Pancreatic ductal adenocarcinoma OXCT1 gemcitabine chemoresistance NF-κB Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Jinsheng Ding Jinsheng Ding Jinsheng Ding Hui Li Hui Li Yang Liu Yang Liu Yongjie Xie Yongjie Xie Jie Yu Huizhi Sun Huizhi Sun Di Xiao Yizhang Zhou Li Bao Hongwei Wang Chuntao Gao OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma |
| description |
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. |
| format |
article |
| author |
Jinsheng Ding Jinsheng Ding Jinsheng Ding Hui Li Hui Li Yang Liu Yang Liu Yongjie Xie Yongjie Xie Jie Yu Huizhi Sun Huizhi Sun Di Xiao Yizhang Zhou Li Bao Hongwei Wang Chuntao Gao |
| author_facet |
Jinsheng Ding Jinsheng Ding Jinsheng Ding Hui Li Hui Li Yang Liu Yang Liu Yongjie Xie Yongjie Xie Jie Yu Huizhi Sun Huizhi Sun Di Xiao Yizhang Zhou Li Bao Hongwei Wang Chuntao Gao |
| author_sort |
Jinsheng Ding |
| title |
OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma |
| title_short |
OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma |
| title_full |
OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma |
| title_fullStr |
OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma |
| title_full_unstemmed |
OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma |
| title_sort |
oxct1 enhances gemcitabine resistance through nf-κb pathway in pancreatic ductal adenocarcinoma |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/948f63ba82084a768da6ea5f421b1b8d |
| work_keys_str_mv |
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| _version_ |
1718444484587421696 |