Huanying Shi , Zimei Wu , Jiafeng Liu , Tianxiao Wang , Zhengchuan Niu , Wenxin Zhang , Bicui Chen , Xiang Mao , Yuxin Huang , Jiyifan Li , Huijie Qi , Xinhai Wang , Lu Chen , Qunyi Li
{"title":"NR1I3通过增强pck1介导的糖异生抑制结直肠癌的生长","authors":"Huanying Shi , Zimei Wu , Jiafeng Liu , Tianxiao Wang , Zhengchuan Niu , Wenxin Zhang , Bicui Chen , Xiang Mao , Yuxin Huang , Jiyifan Li , Huijie Qi , Xinhai Wang , Lu Chen , Qunyi Li","doi":"10.1016/j.cbi.2025.111734","DOIUrl":null,"url":null,"abstract":"<div><div>There is increasing evidence that nuclear receptor subfamily 1 group I member 3 (NR1I3) plays a significant role in the progression of many malignancies. However, it is unclear whether NR1I3 suppresses colorectal cancer (CRC) growth or alters gluconeogenesis. Western blotting, flow cytometry analysis, cell proliferation, colony formation assays, quantitative real-time polymerase chain reaction (qRT‒PCR), gluconeogenesis tests, and animal models were used to examine the functional role of NR1I3 in CRC cells. We found that NR1I3 was frequently downregulated in CRC tissue and that low NR1I3 expression was strongly correlated with poor patient survival. Subsequent in vitro and in vivo functional tests demonstrated that NR1I3 significantly inhibited proliferation and induced apoptosis in CRC cells by arresting the cell cycle in the G2/M phase. We also found that pharmacologically inducing NR1I3 with 6-(4-chlorophenyl) imidazo[2,1-b][1,3] thiazole-5-carbaldehydeO-(3,4-dichlorobenzyl) oxime (CITCO) reduced CRC cell growth and induced apoptosis in vitro and in vivo. Furthermore, we demonstrated that CITCO can influence gluconeogenesis activity by influencing genes in the gluconeogenesis pathway. Notably, NR1I3 increases gluconeogenesis and inhibits glycolysis by interacting with phosphoenolpyruvate carboxykinase 1 (PCK1), the enzyme that limits the rate of gluconeogenesis. This leads to ATP depletion, and cell growth is halted. These findings suggest that NR1I3 inhibits CRC by converting glycolysis to gluconeogenesis via PCK1, suggesting potential indicators and treatment targets for CRC progression.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111734"},"PeriodicalIF":5.4000,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"NR1I3 inhibits colorectal cancer growth by enhancing PCK1-mediated gluconeogenesis\",\"authors\":\"Huanying Shi , Zimei Wu , Jiafeng Liu , Tianxiao Wang , Zhengchuan Niu , Wenxin Zhang , Bicui Chen , Xiang Mao , Yuxin Huang , Jiyifan Li , Huijie Qi , Xinhai Wang , Lu Chen , Qunyi Li\",\"doi\":\"10.1016/j.cbi.2025.111734\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>There is increasing evidence that nuclear receptor subfamily 1 group I member 3 (NR1I3) plays a significant role in the progression of many malignancies. However, it is unclear whether NR1I3 suppresses colorectal cancer (CRC) growth or alters gluconeogenesis. Western blotting, flow cytometry analysis, cell proliferation, colony formation assays, quantitative real-time polymerase chain reaction (qRT‒PCR), gluconeogenesis tests, and animal models were used to examine the functional role of NR1I3 in CRC cells. We found that NR1I3 was frequently downregulated in CRC tissue and that low NR1I3 expression was strongly correlated with poor patient survival. Subsequent in vitro and in vivo functional tests demonstrated that NR1I3 significantly inhibited proliferation and induced apoptosis in CRC cells by arresting the cell cycle in the G2/M phase. We also found that pharmacologically inducing NR1I3 with 6-(4-chlorophenyl) imidazo[2,1-b][1,3] thiazole-5-carbaldehydeO-(3,4-dichlorobenzyl) oxime (CITCO) reduced CRC cell growth and induced apoptosis in vitro and in vivo. Furthermore, we demonstrated that CITCO can influence gluconeogenesis activity by influencing genes in the gluconeogenesis pathway. Notably, NR1I3 increases gluconeogenesis and inhibits glycolysis by interacting with phosphoenolpyruvate carboxykinase 1 (PCK1), the enzyme that limits the rate of gluconeogenesis. This leads to ATP depletion, and cell growth is halted. These findings suggest that NR1I3 inhibits CRC by converting glycolysis to gluconeogenesis via PCK1, suggesting potential indicators and treatment targets for CRC progression.</div></div>\",\"PeriodicalId\":274,\"journal\":{\"name\":\"Chemico-Biological Interactions\",\"volume\":\"421 \",\"pages\":\"Article 111734\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2025-09-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemico-Biological Interactions\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0009279725003643\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemico-Biological Interactions","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0009279725003643","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
NR1I3 inhibits colorectal cancer growth by enhancing PCK1-mediated gluconeogenesis
There is increasing evidence that nuclear receptor subfamily 1 group I member 3 (NR1I3) plays a significant role in the progression of many malignancies. However, it is unclear whether NR1I3 suppresses colorectal cancer (CRC) growth or alters gluconeogenesis. Western blotting, flow cytometry analysis, cell proliferation, colony formation assays, quantitative real-time polymerase chain reaction (qRT‒PCR), gluconeogenesis tests, and animal models were used to examine the functional role of NR1I3 in CRC cells. We found that NR1I3 was frequently downregulated in CRC tissue and that low NR1I3 expression was strongly correlated with poor patient survival. Subsequent in vitro and in vivo functional tests demonstrated that NR1I3 significantly inhibited proliferation and induced apoptosis in CRC cells by arresting the cell cycle in the G2/M phase. We also found that pharmacologically inducing NR1I3 with 6-(4-chlorophenyl) imidazo[2,1-b][1,3] thiazole-5-carbaldehydeO-(3,4-dichlorobenzyl) oxime (CITCO) reduced CRC cell growth and induced apoptosis in vitro and in vivo. Furthermore, we demonstrated that CITCO can influence gluconeogenesis activity by influencing genes in the gluconeogenesis pathway. Notably, NR1I3 increases gluconeogenesis and inhibits glycolysis by interacting with phosphoenolpyruvate carboxykinase 1 (PCK1), the enzyme that limits the rate of gluconeogenesis. This leads to ATP depletion, and cell growth is halted. These findings suggest that NR1I3 inhibits CRC by converting glycolysis to gluconeogenesis via PCK1, suggesting potential indicators and treatment targets for CRC progression.
期刊介绍:
Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.