The Effect of Akt Isoforms in Tumorigenesis and Glucose Homeostasis in Vivo

Germ line Akt1-deficient mice are resistant to cancer development which is driven by hyper-activation of PI3K-Akt signaling in mouse model. However, it is not clear whether Akt1 is required for tumor maintenance, and whether systemic Akt1 deficiency can block tumor progression in the mouse. It is also not known whether Akt1 deficiency could hinder tumorigenesis which is not driven by hyper-activation of PI3K-Akt signaling. Here, we use Akt1f/fRosa26CREERT2 mice, in which Akt1 could be systemically deleted after tamoxifen administration. These mice were crossed with p53-/-mice which are tumor prone. Systemic whole body Akt1-deficient mice substantially increased survival of these mice. Thymic lymphoma cell lines isolated from the mice undergone cell death and cell cycle arrest following by Akt1 deletion. Xenograft tumors of these mice are inhibited after Akt1 deletion. PI3K-Akt signaling is frequently activated in human cancer. Therefore, Akt is a popular target for cancer therapy. However, the long-term effect is not well known since most of tests were done in the xenograft model. Here we used Akt1f/f; Akt2-/-; Rosa26CREERT2 mice and Akt1f/f; Akt2-/-; Albumin-Cre mice to generate combined Akt1 and Akt2 deleted adult mice and liver-specific deleted mice in order to mimic drug therapy condition. Akt1f/f; Akt2-/-; Rosa26CREERT2 adult mice could not survive after tam administration and Akt1hep-/-Akt2-/- mice developed severe diabetes and hepatocellular carcinoma (HCC). Thus, using Akt inhibitors that target both Akt1 and Akt2 need to be aware of the side effects.