The role of PTEN/Akt1/PI3K signaling on the maintenance and viability of prostate cancer stem-like cell populations

Self-renewing tumor initiating cells that are capable of differentiation and responsible for tumor growth have been isolated from cancers and cell lines. If such minor populations are associated with tumor progression, understanding molecular pathways that are required for viability and maintenance of these populations will allow to target these pathways to eradicate tumors that are resistant to existing therapies. In this study we enriched for prostate cancer progenitors (Pr. CPs) expressing cell surface markers CD44/CD133/alpha 2 beta 1 integrin in non-adherent serum-free growth conditions maintained as spheres. Cells grown in these conditions have increased in vivo clonogenic and in vivo tumorigenic potential. microarray analysis of cells grown in sphere conditions compared with long term monolayer culture conditions revealed preferential activation of PI3K/AKT pathway in prostate cancer progenitors. PI3K p110 alpha and beta protein levels were high in sphere condition cultured cells, and PTEN knockdown lead to an increase in Pr.CPs, and to increased clonogenic and tumorigenic potential. Inhibition of Akt1 phosphorylation target FoxO3a lead to inhibition of tumorigenic capacity in vivo for prostate cancer cells. Inhibition of PI3K activity by PI3K inhibitor NVP-BEZ235 lead to a selective inhibition of Pr.CPs, nuclear localization of FoxO3a and increase in GADD45a in prostate cancer cells. Taken together our data strongly suggest that PTEN and PI3K/Akt pathways are critical for prostate cancer stem-like cell maintenance and targeting the PI3K signaling by selective inhibitors may give an incredible advancement in prostate cancer treatment.

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Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, García-Echeverría C, Schultz PG, Reddy VA