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. 2013 Apr 12;3:85. doi: 10.3389/fonc.2013.00085

Figure 1.

Figure 1

(A) Oncogenes and tumor suppressor modulate metabolic reprograming in cancer cells. HIF, hypoxia inducible factor; TIGAR, TP53-induced glycolysis and apoptosis regulator; MYC, Proto oncogene c-Myc; G6PD, glucose-6-phosphate dehydrogenase; GLS2, glutaminase 2. (B) Proposed model highlighting the role of PI3K-Akt-mTOR and Wnt pathways in regulation of the cell cycle progression in cancer cell: according to the presented model, activation of insulin/IGF receptor by nutrients/growth factors activates PI3K-Akt pathway. Akt phosphorylated on T308 activates mTORC1. One of the downstream target of mTORC1, the p70S6Kinase, phosphorylates the serine residues on IRS and inhibits the insulin/IGF signaling in a regulatory feedback control. The activated mTORC1 activates the protein synthesis, but inhibits autophagy. Inhibition of autophagy rescues Dvl and this lead to activation of Wnt pathway. The activated Wnt pathway up regulates cyclin D and C-Myc, which trigger the activation of cell cycle and metabolic reprograming. The metabolic activation in cancer cells leads to the production of reaction oxygen species (ROS), which activate the FoxO. FoxO is the transcription factor of rictor, one of the key components of mTORC2 recognized as the kinase phosphorylating Akt on S473. Rictor also inhibits c-Myc, which according to the present model is required for exit of G1/S restriction point. Akt, protein kinase B (T308, S473 are the phosphorylated sites Threonine 308 and Serine 473 of Akt), c-Myc is the oncoprotein activated by Wnt signaling, FoxO, fork head transcription factors of O group; GLUT, glucose transporter; IGF, insulin growth factor; IRS, insulin receptor substrate; mTORC1, 2, mammalian target of rapamycin (mTOR) Complex 1 and 2, PIP2, phosphoinositide 4,5 bisphosphate; PIP3, phosphoinositide 3,4,5 trisphosphate; rictor, a component of mTORC2; P70S6K, the p70 ribosomal S6K; PTEN, phosphatase and tensin homolog deleted from chromosome ten; ROS, reaction oxygen species; PDPK1 (also abbreviated as PDK1), phosphoinositide dependent protein kinase.