PI3K/Akt pathway and Nanog maintain cancer stem cells in sarcomas

Abstract The self-renewal transcription factor Nanog and the phosphoinositide 3-kinase (PI3K)–Akt pathway are known to be essential for maintenance of mesenchymal stem cells. We evaluated their contribution CD133(+) cancer stem-like cells (CSCs) spheroid-forming in patient-derived cell lines from three human sarcoma subtypes: HT1080 fibrosarcoma, SK-LMS-1 leiomyosarcoma, DDLS8817 dedifferentiated liposarcoma. Levels activated Akt were significantly higher grown as spheroids or sorted CD133 expression enrich CSCs. shRNA knockdown decreased spheroid formation 10- 14-fold, reversed resistance both doxorubicin radiation vitro H1080 flank xenografts. In xenograft model, reduced tumor growth by 34% 45%, respectively, combination 74%. Using a phospho-kinase antibody array, Akt1/2 signaling, regulate Nanog, was found highly compared with monolayer Pharmacologic inhibition using LY294002 CSCs chemotherapy resistance. combined treatment xenografts 73%. Finally, microarray, CD133, phospho-Akt 1.8- 6.8-fold tissue normal tissue. Together, these results indicate that Akt1/2–Nanog is critical cells, supporting further exploration this therapeutic target sarcoma.