Su Pingping, Mao Xiaodan, Ma Jincheng, Huang Lixiang, Yu Lirui, Tang Shuting, Zhuang Mingzhi, Lu Zhonglei, Osafo Kelvin Stefan, Ren Yuan, Wang Xinrui, Lin Xite, Huang Leyi, Huang Xiaoli, Braicu Elena Ioana, Sehouli Jalid, Sun Pengming
Laboratory of Gynecologic Oncology, Department of Gynecology, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical University, Fuzhou, 350001, Fujian, China.
Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.
J Exp Clin Cancer Res. 2023 Oct 20;42(1):274. doi: 10.1186/s13046-023-02834-7.
Tumor cells can resist chemotherapy-induced pyroptosis through glycolytic reprogramming. Estrogen-related receptor alpha (ERRα) is a central regulator of cellular energy metabolism associated with poor cancer prognosis. Herein, we refine the oncogenic role of ERRα in the pyroptosis pathway and glycolytic metabolism.
The interaction between ERRα and HIF-1α was verified using co-immunoprecipitation. The transcriptional binding sites of ERRα and NLRP3 were confirmed using dual-luciferase reporter assay and cleavage under targets and tagmentation (CUT&Tag). Flow cytometry, transmission electron microscopy, scanning electron microscopy, cell mito stress test, and extracellular acidification rate analysis were performed to investigate the effects of ERRα on the pyroptosis pathway and glycolytic metabolism. The results of these experiments were further confirmed in endometrial cancer (EC)-derived organoids and nude mice. In addition, the expression of ERRα-related pyroptosis genes was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus database.
Triggered by a hypoxic microenvironment, highly expressed ERRα could bind to the promoter of NLRP3 and inhibit caspase-1/GSDMD signaling, which reduced inflammasome activation and increased pyroptosis resistance, thereby resulting in the resistance of cancer cells to cisplatin. Moreover, ERRα activated glycolytic rate-limiting enzyme to bridge glycolytic metabolism and pyroptosis in EC. This phenomenon was further confirmed in EC-derived organoids and nude mice. CUT & Tag sequencing and The Cancer Genome Atlas database analysis showed that ERRα participated in glycolysis and programmed cell death, which resulted in EC progression.
ERRα inhibits pyroptosis in an NLRP3-dependent manner and induces glycolytic metabolism, resulting in cisplatin resistance in EC cells.
肿瘤细胞可通过糖酵解重编程抵抗化疗诱导的细胞焦亡。雌激素相关受体α（ERRα）是与癌症预后不良相关的细胞能量代谢的核心调节因子。在此，我们细化了ERRα在细胞焦亡途径和糖酵解代谢中的致癌作用。
采用免疫共沉淀法验证ERRα与HIF-1α之间的相互作用。采用双荧光素酶报告基因检测法和靶向切割与标签化技术（CUT&Tag）确定ERRα与NLRP3的转录结合位点。进行流式细胞术、透射电子显微镜、扫描电子显微镜、细胞线粒体应激试验和细胞外酸化率分析，以研究ERRα对细胞焦亡途径和糖酵解代谢的影响。这些实验结果在子宫内膜癌（EC）来源的类器官和裸鼠中得到进一步证实。此外，使用癌症基因组图谱和基因表达综合数据库分析ERRα相关细胞焦亡基因的表达。
在缺氧微环境的触发下，高表达的ERRα可与NLRP3启动子结合并抑制caspase-1/GSDMD信号传导，从而减少炎性小体激活并增加细胞焦亡抗性，进而导致癌细胞对顺铂产生抗性。此外，ERRα激活糖酵解限速酶，在EC中连接糖酵解代谢和细胞焦亡。这一现象在EC来源的类器官和裸鼠中得到进一步证实。CUT&Tag测序和癌症基因组图谱数据库分析表明，ERRα参与糖酵解和程序性细胞死亡，从而导致EC进展。
ERRα以NLRP3依赖的方式抑制细胞焦亡并诱导糖酵解代谢，导致EC细胞产生顺铂抗性。
