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. 2021 Jun 11;13(12):2922. doi: 10.3390/cancers13122922

Figure 2.

Figure 2

The effects of mTOR and inhibition of mTOR and aerobic glycolysis in Stk11−/−NIC (Lkb1−/−NIC) mouse model of HER2-positive breast cancer. The overexpression of ErbB2 in the breast tumors of the HER2-positive breast cancer mouse model (NIC) shows up-regulation of ERK, Akt, and mTOR signaling as well as aerobic glycolysis; however, deficiency of LKB1 expression in NIC mice (Lkb1−/−NIC) leads to hyperactivation of mTOR (indicated by the green arrow) that enhances aerobic glycolysis. In Lkb1−/−NIC mammary gland tumors, inhibition of mTORC1 and mTORC2 via AZD8055 prevents mTORC1-dependent phosphorylation of S6K and mTORC2-dependent Akt phosphorylation on S473, inhibits cell proliferation, and reduces aerobic glycolysis through down-regulation of glycolytic enzymes. Prolonged inhibition of mTOR activates pro-survival pathways in a pERK-p90RSK-dependent manner (indicated by the red, dashed arrow). In addition, inhibition of aerobic glycolysis via 2-deoxy-D-glucose (2-DG) does not affect mTOR activity but promotes activation of AMPK and PI3K. The addition of 2-DG to AZD8055 treatment prevented the AZD8055 induction of ERK activation.