Abstract 3344: Akt1 and Akt3 exert opposing roles in the regulation of vascular tumor growth

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Abstract Vascular tumors are endothelial cell neoplasms with a wide spectrum of clinical presentations, ranging from benign infantile hemangiomas in children to low-grade malignant hemangioendotheliomas and highly aggressive angiosarcomas in adults. To date, the cellular and molecular mechanisms leading to vascular tumor formation are poorly understood, and current therapies, particularly those for malignant vascular tumors, have not significantly improved the clinical outcome. We examined the growth regulatory pathways in vascular tumors, and showed that human vascular tumors have increased Akt activation, and constitutive activation of Akt1 in endothelial cells is sufficient to drive de novo vascular tumor formation in a transgenic mouse model. Importantly, we have uncovered the opposing functions of Akt isoforms in this regulation, in which Akt1 promotes, whereas Akt3 inhibits tumor endothelial cell migration and growth in in vitro and in vivo tumor models. Consistent with these findings, we observed reduced levels of Akt3 expression in human vascular tumors. Mechanistically, Akt3 blocks tumor cell migration and growth by inhibiting p70 S6-Kinase (S6K) activation, and Akt3 does so in part by modulating the levels of Rictor, a component of the mammalian target of rapamycin complex-2. S6K in turn exerts negative feedback regulation on Akt3 expression. Moreover, vascular tumor cells with Akt3 knockdown have increased S6K signaling, and are sensitized to a novel S6K inhibitor. Our findings provide a new perspective on Akt signaling, in which there are “check-and-balance” functions by different Akt isoforms to modulate the overall Akt signaling output. These studies also highlight the potential clinical utility of treating malignant vascular tumors, such as angiosarcomas, with agents that effectively block the S6K pathway. Citation Format: Thuy L. Phung, Qi Xue, Sokha Nhek, Damien Gerald, Carole Perruzzi, Sriram Ayyaswamy, Wa Du, Sandaruwan Geeganage, Laura Benjamin. Akt1 and Akt3 exert opposing roles in the regulation of vascular tumor growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3344. doi:10.1158/1538-7445.AM2014-3344