2. Academic Validation
  3. Akt1 and akt3 exert opposing roles in the regulation of vascular tumor growth

Akt1 and akt3 exert opposing roles in the regulation of vascular tumor growth

  • Cancer Res. 2015 Jan 1;75(1):40-50. doi: 10.1158/0008-5472.CAN-13-2961.
Thuy L Phung 1,  Wa Du 2,  Qi Xue 3,  Sriram Ayyaswamy 2,  Damien Gerald 3,  Zeus Antonello 4,  Sokha Nhek 3,  Carole A Perruzzi 3,  Isabel Acevedo 4,  Rajesh Ramanna-Valmiki 2,  Paul Rodriguez-Waitkus 2,  Ladan Enayati 2,  Marcelo L Hochman 5,  Dina Lev 6,  Sandaruwan Geeganage 3,  Laura E Benjamin 7
Affiliations

Affiliations

  • 1 Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas. laura.benjamin@lilly.com tphung@bcm.edu.
  • 2 Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas.
  • 3 Eli Lilly and Company, Indianapolis, Indiana.
  • 4 Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
  • 5 Hemangioma International Treatment Center, Charleston, South Carolina.
  • 6 Department of Cancer Biology, MD Anderson Cancer Center, Houston, Texas.
  • 7 Eli Lilly and Company, Indianapolis, Indiana. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. laura.benjamin@lilly.com tphung@bcm.edu.
PMID: 25388284 DOI: 10.1158/0008-5472.CAN-13-2961
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.

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