The effect Akt2 deletion on tumor development in Pten+/− mice

Abstract

The serine/threonine kinase Akt is frequently activated in human cancers and is considered an attractive therapeutic target. However, the relative contributions of the different Akt isoforms to tumorigenesis, and the effect of their deficiencies on cancer development are not well understood. We had previously shown that Akt1 deficiency is sufficient to markedly reduce the incidence of tumors in Pten+/− mice. Particularly, Akt1 deficiency inhibits endometrial carcinoma and prostate neoplasia in Pten+/− mice. Here, we analyzed the effect of Akt2 deficiency on the incidence of tumors in Pten+/− mice. Relative to Akt1, Akt2 deficiency had little-to-no effect on the incidence of prostate neoplasia, endometrial carcinoma, intestinal polyps and adrenal lesions in Pten+/− mice. However, Akt2 deficiency significantly decreased the incidence of thyroid tumors in Pten+/−, which correlates with the relatively high level of Akt2 expression in the thyroid. Thus, unlike Akt1 deletion, Akt2 deletion is not sufficient to markedly inhibit tumorigenesis in Pten+/− mice in most tested tissues. The relatively small effect of Akt2 deletion on the inhibition of tumorigenesis in Pten+/− mice could be explained, in part, by an insufficient decrease in total Akt activity, due to the relatively lower Akt2 versus Akt1 expression, and relatively high blood insulin levels in Pten+/−Akt2−/− mice. The relatively high blood insulin levels in Pten+/−Akt2−/− mice may elevate the activity of Akt1, and possibly Akt3, thus, limiting the reduction of total Akt activity and preventing this activity from dropping to a threshold level required to inhibit tumorigenesis.

In Vivo Role of INPP4B in Tumor and Metastasis Suppression through Regulation of PI3K–AKT Signaling at Endosomes

“…Previous studies have shown that Akt2 deficiency had little-to-no effect on the tumor spectrum in Pten +/− mice, and only specifically significantly decreased the incidence of thyroid tumors in Pten +/− mice (18), suggesting that AKT2 might play an oncogenic role in thyroid cancer. Recent studies have shown that AKT2 phosphorylates its substrates on both endosomes and the plasma membrane (19).…”

“…In the context of breast cancer, AKT2 has been implicated in metastasis, whereas AKT1 suppresses metastatic dissemination (30). Interestingly, signaling through AKT2 is critical for the development of thyroid neoplasms in Pten +/− mice (18). Specifically, loss of Akt2 in Pten +/− mice rescues the development of thyroid adenomas in this model (18).…”

“…Interestingly, signaling through AKT2 is critical for the development of thyroid neoplasms in Pten +/− mice (18). Specifically, loss of Akt2 in Pten +/− mice rescues the development of thyroid adenomas in this model (18). Furthermore, genomic amplification of AKT2 is frequently observed in FTC, but not in anaplastic thyroid carcinoma (31).…”

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

“…The germ line deletion of Akt1 in the mouse does not have adverse physiological consequences, and Akt1 −/− mice live significantly longer than control WT mice (Chen et al, 2006). By contrast germ line deletion of Akt2 induces insulin resistance and does not inhibit tumor development in mouse models of breast cancer and in Pten+/− mice (Maroulakou et al, 2007; Xu et al, 2012). However, studies using germ line deletions of Akt isoforms cannot determine if Akt is required for tumor progression and do not emulate drug therapy.…”

PTEN-Deficient Tumors Depend on AKT2 for Maintenance and Survival

“…Similarly, mice lacking Akt1 are protected from tumorigenesis induced by PTEN loss (24). Curiously, a more recent study indicated that inactivation of Akt2 has little or no consequence on prostate neoplasia, explained in part by the relatively little impact of Akt2 loss on total Akt activity and also an increase in blood insulin levels (25). By contrast, Akt2 is required for proliferation and invasive migration of PTEN-deficient glioblastoma (26, 27).…”