NDLI: Aberrant AKT activation drives well-differentiated liposarcoma

Content Provider	PubMed Central
Author	Gutierrez, Alejandro Snyder, Eric L. Adrian, Marino-enriquez Zhang, Yi-xiang Stefano, Sioletic Elena, Kozakewich Ruta, Grebliunaite Ou, Wen-bin Sicinska, Ewa Raut, Chandrajit P. Demetri, George D. Perez-atayde, Antonio R. Wagner, Andrew J. Fletcher, Jonathan A. Fletcher, Christopher D. M. Look, A. Thomas
Abstract	Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebrafish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in p53 wild-type zebrafish, 6% in p53 heterozygotes, and 29% in p53-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS pathogenesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphorylation in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma.
Related Links	http://dx.doi.org/10.1073/pnas.1106127108
Ending Page	16391
Page Count	6
Starting Page	16386
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	39
Volume Number	108
Language	English
Publisher	National Academy of Sciences
Publisher Date	2011-09-27
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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