Whole-gene CRISPR/cas9 library screen revealed targeting STAT6 increased the sensitivity of liver cancer to celecoxib via inhibiting arachidonic acid shunting
文献类型：期刊论文
| 作者 | Hu, Chujiao2,3,4,5; Zeng, Zhirui5; Bao, Xin5; Li, Dahuan5; Tai, Huading5; Zeng, Haohao5; Luo, Cheng4,6,7; Tang, Lei2,3; Chen, Tengxiang1,5; Zuo, Shi1,8 |
| 刊名 | CELL COMMUNICATION AND SIGNALING
 |
| 出版日期 | 2025-08-28 |
| 卷号 | 23期号:1页码:18 |
| 关键词 | Liver cancer Celecoxib AA shunting STAT6 |
| DOI | 10.1186/s12964-025-02374-x |
| 英文摘要 | Celecoxib, a selective COX-2 inhibitor, has demonstrated anti-liver cancer effects in various preclinical models and clinical traits. However, prolonged use of celecoxib can lead to drug resistance, necessitating higher doses to maintain efficacy, which often results in severe side effects, limiting its clinical application. This study aimed to identify strategies to overcome celecoxib resistance in liver cancer. CRISPR/Cas9 screening revealed that liver cancer cells compensated for celecoxib treatment by upregulating ALOX and CYP enzymes, facilitating AA metabolism to produce alternative downstream products. STAT6 was identified as a key regulator of ALOX15, ALOX12, and CYP2E1, acting as a resister to celecoxib. Celecoxib stimulation leaded to increased phosphorylation of STAT6, enhanced binding to the promoters of target genes such as ALOX15, and upregulation of downstream gene expression. Knockdown of STAT6 significantly enhanced celecoxib sensitivity in vitro and in vivo by blocking AA shunting mediated by these enzymes. Furthermore, AS1517499, a STAT6 inhibitor, showed strong synergy with celecoxib in liver cancer cells by inhibiting AA shunting. In conclusion, targeting STAT6 enhances the efficacy of celecoxib in liver cancer by suppressing AA shunting. The combination of AS1517499 and celecoxib holds promise as a novel therapeutic strategy for liver cancer. |
| WOS关键词 | COLON-CANCER ; 5-LIPOXYGENASE ; INFLAMMATION ; ACTIVATION ; LICOFELONE ; THERAPY ; PATHWAY |
| 资助项目 | the National Natural Science Foundation of China[[2022] 020] ; Continuous Support Fund for Excellent Scientific Research Platform of Colleges and Universities in Guizhou Province[gyfykyc-2023-01] ; National Natural Science Foundation Cultivation Project of the Affiliated Hospital of Guizhou Medical University[82473969] ; National Natural Science Foundation Cultivation Project of the Affiliated Hospital of Guizhou Medical University[82160665] ; National Natural Science Foundation Cultivation Project of the Affiliated Hospital of Guizhou Medical University[82260535] ; National Natural Science Foundation of China[2022M720929] ; National Natural Science Foundation of China[2024M750674] ; China Postdoctoral Science Foundation[[2023]002] ; China Postdoctoral Science Foundation[ZK[2024]] ; China Postdoctoral Science Foundation[061] ; Guizhou High-level Innovative Talents Supporting Program (GCC) |
| WOS研究方向 | Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:001560144400002 |
| 出版者 | BMC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321345]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Tang, Lei; Chen, Tengxiang; Zuo, Shi |
| 作者单位 | 1.Guizhou Med Univ, Affiliated Hosp, Precis Med Res Inst Guizhou, Guiyang, Peoples R China 2.Guizhou Med Univ, State Key Lab Discovery & Utilizat Funct Component, Guiyang, Peoples R China 3.Guizhou Prov Engn Technol Res Ctr Chem Drug R&D, Guiyang, Peoples R China 4.Guizhou Med Univ, Sch Pharmaceut Sci & technol, Guiyang, Peoples R China 5.Guizhou Med Univ, Transformat Engn Res Ctr Chron Dis Diag & Treatmen, Sch Basic Med Sci, Dept Physiol, Guiyang, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 7.Guizhou Med Univ, Guizhou Prov Key Lab Digest Syst Dis, Affiliated Hosp, Guiyang, Peoples R China 8.Guizhou Med Univ, Affiliated Hosp, Dept Hepatobiliary Surg, Guiyang, Peoples R China |
| 推荐引用方式 GB/T 7714 | Hu, Chujiao,Zeng, Zhirui,Bao, Xin,et al. Whole-gene CRISPR/cas9 library screen revealed targeting STAT6 increased the sensitivity of liver cancer to celecoxib via inhibiting arachidonic acid shunting[J]. CELL COMMUNICATION AND SIGNALING,2025,23(1):18. |
| APA | Hu, Chujiao.,Zeng, Zhirui.,Bao, Xin.,Li, Dahuan.,Tai, Huading.,...&Zuo, Shi.(2025).Whole-gene CRISPR/cas9 library screen revealed targeting STAT6 increased the sensitivity of liver cancer to celecoxib via inhibiting arachidonic acid shunting.CELL COMMUNICATION AND SIGNALING,23(1),18. |
| MLA | Hu, Chujiao,et al."Whole-gene CRISPR/cas9 library screen revealed targeting STAT6 increased the sensitivity of liver cancer to celecoxib via inhibiting arachidonic acid shunting".CELL COMMUNICATION AND SIGNALING 23.1(2025):18. |
入库方式： OAI收割
来源：上海药物研究所
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