High levels of p110δ PI3K expression in solid tumor cells suppress PTEN activity, generating cellular sensitivity to p110δ inhibitors through PTEN activation

Class IA PI3K isoforms have divergent, nonredundant cell biological roles. In untransformed cells and tissues, p110 alpha and p110 beta are ubiquitously expressed, whereas p110 delta expression is highly enriched in leukocytes. High levels of p110 delta expression have been documented in some solid tumor cell lines, but the functional role is unknown. This study aimed to elucidate the link between elevated expression of p110 delta PI3K and cancer. We report that in breast and prostate cancer cells that contain leukocyte levels of p110 delta, p110 delta activity dampens the activity of the PTEN tumor suppressor. Indeed, inactivation of p110 delta in these cells led to PTEN activation, suppression of Akt phosphorylation, and inhibition of cell proliferation, with inhibition of PTEN activity being able to counterbalance p110 delta inactivation. Likewise, forced overexpression of p110 delta in cells with low p110 delta expression reduced PTEN activity, resulting in increased Akt phosphorylation. Our data indicate that the oncogenic potential of p110 delta PI3K overexpression might at least partially act through PTEN inactivation, and that p110 delta-selective PI3K inhibitors can have a dual antitumor mechanism, namely by directly inhibiting p110 delta signaling and by a broader inhibition of class I PI3K activity through PTEN activation. These data may have important implications in the intervention of breast cancer.-Tzenaki, N., Andreou, M., Stratigi, K., Vergetaki, A., Makrigiannakis, A., Vanhaesebroeck, B., Papakonstanti, E. A. High levels of p110 delta PI3K expression in solid tumor cells suppress PTEN activity, generating cellular sensitivity to p110 delta inhibitors through PTEN activation. FASEB J. 26, 2498-2508 (2012). www.fasebj.org