ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer

• Published in: Journal of experimental & clinical cancer research Vol. 42; no. 1; p. 274
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England BioMed Central 20-10-2023; BMC
• Subjects: Animals; Apoptosis; Cancer therapies; Caspase 1 - genetics; Caspase 1 - metabolism; Caspase 1 - pharmacology; Cell death; Cell growth; Chemotherapy; Cisplatin - pharmacology; Cisplatin resistance; Drugs; Endometrial cancer; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - genetics; Enzymes; ERRalpha Estrogen-Related Receptor; ERRα; Estrogens; Female; Flow cytometry; Glycolysis; Humans; Hypoxia; Medical prognosis; Metabolic reprogramming; Metabolism; Metastasis; Mice; Mice, Nude; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Phosphate-Binding Proteins - genetics; Phosphate-Binding Proteins - metabolism; Phosphate-Binding Proteins - pharmacology; Pore Forming Cytotoxic Proteins - metabolism; Pyroptosis; Tumor Microenvironment; Tumors; United States > US; Massachusetts; China; Pyroptosis; Cisplatin resistance; Metabolic reprogramming; Endometrial cancer; ERRα
• ISSN: 1756-9966; 0392-9078; 1756-9966
• 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.