Fig. 1

The interactions between Sestrin2 and different signaling pathways in cancer. P53 is a major upstream molecule for Sestrin2. Oxidative stress and P53 can increase Sestrin2 expression. In response, Sestrin2 liberates Nrf2 from Keap1 sequestration. Activated Nrf2 binds to ARE and promotes the gene expression of several antioxidants such as Sestrin2, Ho-1, NQO1, GSH, SOD, GPx, and CAT. Sestrin2 is a leucine sensitive factor for mTORC1. Sestrin2 attenuates the inhibitory effect of GATOR2 on GATOR1. GATOR1 suppresses RagB to inhibit mTORC1. Further, Sestrin2 activates the LKB1/AMPK pathway which can inhibit mTORC1 through TSC2. mTORC1 inhibition can enormously abrogate the oncogenic effects of the PI3K/AKT/mTORC1 pathway. mTORC1 inhibition facilitates autophagy and impedes ribosomal protein synthesis. Several of these proteins are needed for cancer cells metabolism and cell cycle progression and their absence halts cancer cells proliferation. Activation of the LKB1/AMPK pathway can also effectively downregulate HIF-1α which is involved in intra-tumor angiogenesis, Warburg effect, epithelial-mesenchymal transition, and tumor cells immune evasion