Fig. 4.

The pathways of metabolite sensing of glutamate, leucine and ariginie. It includes three pathways of metabolite sensing of protein. Glutamic acid produced by glutamine hydrolysis can be exported from tumor cells through transporters such as XCT. When Xct is functional and glutamate is exported, glutamate can function through multiple types of receptor signals, thereby reducing intercellular adhesion and increasing tumor erosion. Leucine concentration increasing leads to a migration from leucine to the lysosome, where it facilitates the proper nucleotide loading of the Rag GTPase heterodimer complex, which stimulates the activity of mTORC1. When activated, mTOR will phosphorylate S6K1 and 4E-BP1, and the phosphorylated S6K1 (phosphorylates p70-S6 kinase 1) and 4E-BP1 (4E binding protein 1) activate the protein translation initiation complex, then promote protein synthesis. Arginine can be transported to NO through NOS in cells. Below 150 nm, NO stimulates the proliferation of tumor; above this concentration, NO promotes cancer cell death: When between 1nm-30nm, NO activates protein kinase G, whose role is to promote angiogenesis and endothelial cell proliferation. Between 30 and 100 nm, NO activates other downstream kinases, such as protein kinase B (PKB or AKT), and stimulates proliferation and anti-apoptotic responses in tumor cells. Between 100 and 150 nm, NO stabilizes hif-1α, thereby increasing the production of vascular endothelial growth factor (VEGF in endothelial cells and cancer cells, leading to angiogenesis of tumor. Above 150 nm, the tumor suppressor gene p53 will be phosphorylated and activated, mitogen-activated protein kinase 1 (mkp1) will be overexpressed, and cellular respiration will be inhibited, leading to tumor cell apoptosis