Akt1 and Akt3 Exert Opposing Roles in the Regulation of Vascular Tumor Growth

Abstract

Vascular tumors are endothelial cell neoplasms whose mechanisms of tumorigenesis are poorly understood. Moreover, current therapies, particularly those for malignant lesions, have little beneficial effect on clinical outcomes. In this study, we show that endothelial activation of the Akt1 kinase is sufficient to drive de novo tumor formation. Mechanistic investigations uncovered opposing functions for different Akt isoforms in this regulation, where Akt1 promotes and Akt3 inhibits vascular tumor growth. Akt3 exerted negative effects on tumor endothelial cell growth and migration by inhibiting activation of the translation regulatory kinase S6-Kinase (S6K) through modulation of Rictor expression. S6K in turn acted through a negative feedback loop to restrain Akt3 expression. Conversely, S6K signaling was increased in vascular tumor cells where Akt3 was silenced, and the growth of these tumor cells was inhibited by a novel S6K inhibitor. Overall, our findings offer a preclinical proof of concept for the therapeutic utility of treating vascular tumors, such as angiosarcomas, with S6K inhibitors. Cancer Res; 75(1); 40-50. Ó2014 AACR.

The critical role of Akt in cardiovascular function

“…This isoform specific cell development causes smaller brain sizes in Akt3 knockout mice, but not in Akt1 knockout mice [19]. In addition, Akt1 promotes endothelial neoplasms while Akt3 acts in an opposite manner [20]. The reduction of phosphorylation of endothelial nitric oxide synthase (eNOS) by Akt1 knockout can be compensated by Akt2, though phosphorylation of angiogenic substrate by Akt1 seems to be essential for angiogenesis [21].…”

Akt3 inhibits adipogenesis and protects from diet-induced obesity via signaling pathway

“…Phenotypic analysis of the individual Akt isoform deletions and combined deletions in the mouse suggest compensatory and complementary roles of isoforms (5). However, the 3 isoforms also have distinct, even opposite, functions -even at the cellular level (6,7). All 3 isoforms of Akt are expressed in adipocytes (8).…”

Regulation of PtdIns(3,4,5)P3/Akt signalling by inositol polyphosphate 5-phosphatases

“…Isoformspecific roles in cancer are also emerging. Akt1 inhibits but Akt2 promotes breast cancer metastasis in murine models [34,35]; and Akt1 enhances whereas Akt3 inhibits the growth of vascular tumours [36]. These isoform-specific signalling cascades are complex and the reader is referred to recent reviews ( [37][38][39][40][41]).…”