Systemic Akt1 Deletion after Tumor Onset in p53−/− Mice Increases Lifespan and Regresses Thymic Lymphoma Emulating p53 Restoration

Abstract

Summary Akt is frequently activated in human cancers. However, it is unknown whether systemic inhibition of a single Akt isoform, could regress cancer progression in cancers that are not driven by Akt activation. We systemically deleted Akt1, after tumor onset, in p53−/− mice, which develop tumors independently of Akt activation. Systemic Akt1 deletion regresses thymic lymphoma in p53−/− mice emulating p53 restoration. Furthermore, pharmacological inhibition of Akt selectively kills thymic lymphoma cells and not primary thymocytes. Mechanistically, Akt1 inhibition in p53−/− thymic lymphoma inhibits Skp2 expression, and induces FasL, which is the primary cause of cell death. Skp2 exerts resistance to cell death by antagonizing the induction of FasL and reducing FAS expression, which is linked to cyclin D1 expression. The results established a new paradigm whereby systemic Akt1 inhibition is sufficient to regress tumors that are not driven by Akt activation, and a new mechanism of cell survival by Skp2.

Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms

“…Thus, upon injection of tamoxifen, Cre is activated to systemically delete the floxed allele (Ventura et al, 2007). We have shown that Akt1 can be systemically deleted in these adult mice following injection of tamoxifen and that the deletion did not elicit any overt phenotype but was able to regress thymic lymphoma in Trp53 −/− mice (Yu et al, 2015). Akt1 f/f ;R26Cre ERT2 mice were crossed with either Akt2 −/− or Akt3 −/− mice to generate either Akt1 f/f ;Akt2 −/− ;R26Cre ERT2 or Akt1 f/f ;Akt3 −/− ;R26Cre ERT2 mice (Figure 1A).…”

“…Inhibitors of Akt and PI3K are being used for cancer therapy (Dienstmann et al, 2014; Fruman and Rommel, 2014), and the germ line deletion of Akt1 in mice was reported to significantly impair tumor development in several mouse models of cancer (Chen et al, 2006; Hollander et al, 2011; Ju et al, 2007; Maroulakou et al, 2007; Skeen et al, 2006). Moreover, systemic deletion of Akt1 after tumor onset in Trp53 −/− mice halts and regresses thymic lymphoma (Yu et al, 2015). By contrast our results showed that hepatic inactivation of Akt1 and Akt2 induces HCC with markedly faster onset than by the activation of Akt through hepatic Pten deletion, which occurs 75 weeks after birth (Horie et al, 2004).…”

“…Akt1 f/f mice were generated by Ozgene (Australia), and the generation of Akt1 f/f ;R26RCre ERT2 mice has been described elsewhere (Yu et al, 2015). Akt1 f/f ;Akt2 f/f , and Akt1 f/f ;Akt2 f/f ;FoXo1 f/f mice have been previously described (Lu et al, 2012).…”

“…The generation of Akt1 f/f ;Akt2 f/f ;R26Cre ERT2 was performed by crossing Akt1 f/f ;R26Cre ERT2 in the FVB background with Akt2 f/f mice in the FVB background. Systemic injection of AAV into Akt1 f/f ;Akt2 f /f or Akt1 f/f ;Akt2 f/f ;Foxo1 f/f mice was conducted as previously described (Lu et al, 2012)Tamoxifen injection for systemic activation of Cre recombinase has been previously described (Yu et al, 2015). All animal experiments were approved by the University of Illinois at Chicago Institutional Animal Care and Use Committee, as required by United States Animal Welfare Act, and the NIH’s policy.…”

“…We recently showed that systemic deletion of Akt1 in adult p53 −/− mice after tumor onset halted and regressed thymic lymphoma developed in these mice (Yu et al, 2015). In the present studies we determined the consequences of combined Akt isoforms deletion in adult mice.…”