The TRPM7 channel reprograms cellular glycolysis to drive tumorigenesis and angiogenesis

• Published in: Cell death & disease Vol. 14; no. 3; p. 183
• Main Authors: Wu, Wanzhou, Wang, Xuan, Liao, Longsheng, Chen, Jing, Wang, Yue, Yao, Meilian, Zhu, Lingping, Li, Jiayu, Chen, Alex F., Zhang, Guogang, Zhang, Zheng, Bai, Yongping
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06-03-2023; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/109; 14/19; 38/39; 38/77; 38/89; 42/34; 631/67/2327; 631/80/86/2372; 82/80; 96/44; 96/95; Angiogenesis; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Calcineurin; Calcium influx; Calcium signalling; Cancer; Cancer therapies; Carcinogenesis - genetics; Cardiology; Cell Biology; Cell Culture; Cell growth; Cell Transformation, Neoplastic; Clonal deletion; Cyclic AMP response element-binding protein; Endothelial Cells; Geriatrics; Glucose; Glucose metabolism; Glycolysis; Hospitals; Humans; Immunology; Intracellular signalling; Kinases; Laboratory animals; Life Sciences; Medical research; Medicine; Metabolism; Metabolomics; Mice; Oxidative phosphorylation; Phosphorylation; Protein Serine-Threonine Kinases; Proteins; Signal transduction; Statistical analysis; Transcription; Transcription activation; Transient receptor potential proteins; TRPM Cation Channels - genetics; Tumorigenesis; Tumors; Xenografts
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-05701-7

Cancer or endothelial cells preferably catabolize glucose through aerobic glycolysis rather than oxidative phosphorylation. Intracellular ionic signaling has been shown to regulate glucose metabolism, but the underlying ion channel has yet to be identified. RNA-seq, metabolomics and genetic assay revealed that the TRPM7 channel regulated cellular glycolysis. Deletion of TRPM7 suppressed cancer cell glycolysis and reduced the xenograft tumor burden. Deficiency of endothelial TRPM7 inhibited postnatal retinal angiogenesis in mice. Mechanistically, TRPM7 transcriptionally regulated the solute carrier family 2 member 3 (SLC2A3, also known as GLUT3) via Ca
2+
influx-induced calcineurin activation. Furthermore, CREB-regulated transcription coactivator 2 (CRTC2) and CREB act downstream of calcineurin to relay Ca
2+
signal to SLC2A3 transcription. Expression of the constitutively active CRTC2 or CREB in TRPM7 knockout cell normalized glycolytic metabolism and cell growth. The TRPM7 channel represents a novel regulator of glycolytic reprogramming. Inhibition of the TRPM7-dependent glycolysis could be harnessed for cancer therapy.