Akt1 and akt3 exert opposing roles in the regulation of vascular tumor growth.
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.
Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas. laura.benjamin@lilly.com tphung@bcm.edu.
Thuy L
TL
Phung
Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas.
Wa
W
Du
Eli Lilly and Company, Indianapolis, Indiana.
Qi
Q
Xue
Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas.
Sriram
S
Ayyaswamy
Eli Lilly and Company, Indianapolis, Indiana.
Damien
D
Gerald
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Zeus
Z
Antonello
Eli Lilly and Company, Indianapolis, Indiana.
Sokha
S
Nhek
Eli Lilly and Company, Indianapolis, Indiana.
Carole A
CA
Perruzzi
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Isabel
I
Acevedo
Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas.
Rajesh
R
Ramanna-Valmiki
Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas.
Paul
P
Rodriguez-Waitkus
Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas.
Ladan
L
Enayati
Hemangioma International Treatment Center, Charleston, South Carolina.
Marcelo L
ML
Hochman
Department of Cancer Biology, MD Anderson Cancer Center, Houston, Texas.
Dina
D
Lev
Eli Lilly and Company, Indianapolis, Indiana.
Sandaruwan
S
Geeganage
Eli Lilly and Company, Indianapolis, Indiana. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. laura.benjamin@lilly.com tphung@bcm.edu.
Laura E
LE
Benjamin
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019043:Vascular Neoplasms / Q000201:enzymology* / Q000473:pathology*
C494918:AKT1 protein, human; C491754:AKT3 protein, human; C514862:Akt1 protein, mouse; C491753:Akt3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt