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

Abstract

Class IA PI3K isoforms have divergent, nonredundant cell biological roles. In untransformed cells and tissues, p110α and p110β are ubiquitously expressed, whereas p110δ expression is highly enriched in leukocytes. High levels of p110δ 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 p110δ PI3K and cancer. We report that in breast and prostate cancer cells that contain leukocyte levels of p110δ, p110δ activity dampens the activity of the PTEN tumor suppressor. Indeed, inactivation of p110δ 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 p110δ inactivation. Likewise, forced overexpression of p110δ in cells with low p110δ expression reduced PTEN activity, resulting in increased Akt phosphorylation. Our data indicate that the oncogenic potential of p110δ PI3K overexpression might at least partially act through PTEN inactivation, and that p110δ-selective PI3K inhibitors can have a dual antitumor mechanism, namely by directly inhibiting p110δ 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.

Phosphoinositide 3-kinase p110δ promotes lumen formation through the enhancement of apico-basal polarity and basal membrane organization

“…p110δ is known to be mainly expressed in cells of hematopoietic lineage, and although several studies have reported expression in epithelial cells 28-29 , its possible role in epithelial morphogenesis has not been determined. Thus we decided to further characterize the p110δ protein expression and localization in MDCK cells.…”

PI3Kδ Inhibition Augments the Efficacy of Rapamycin in Suppressing Proliferation of Epstein−Barr Virus (EBV)+ B Cell Lymphomas

“…Class IA PI3K are heterodimers consisting of a p110 α, β, or δ catalytic subunit and a p85 regulatory subunit. Whereas p110α and β are expressed in all cells, p110δ is expressed mainly in leukocytes but is also expressed in many cancers (30, 31). mTOR is a serine threonine kinase that acts as a central node to integrate signals received from the PI3K and Ras pathways to coordinate protein and lipid biosynthesis and growth factor induced cell cycle progression (32).…”

Molecules in medicine mini-review: isoforms of PI3K in biology and disease

“…This therapeutic potential for p110β inhibition is illustrated by the observation that mice lacking PI3Kβ activity are protected in an experimental model of autoimmune skin blistering disease [34]. PI3Kδ p110δ, like p110γ, is highly expressed in leukocytes [36,37] but is also present at intermediate levels in other tissues, such as neurons [38] and some transformed epithelial cells [39,40]. Its predominant expression in the haematopoietic compartment correlates with a variety of immune functions, mainly in the adaptive immune system, with important roles in B-and T-cells [41], but also in mast cells [42] and myeloid cells (such as neutrophils and macrophages) [43,34].…”

“…Like wild-type p110α and p110β, p110δ may become activated by mutations in its associated p85 regulatory subunit [26]. Whereas the expression level of p110δ in leukocytes does not appear to significantly increase upon transformation, some solid tumour cell lines express high levels of the p110δ protein, where it might contribute to migration and epithelial polarity [48,39,40,49,50].…”