title: 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.
authors.affiliation: Department of Biochemistry, School of Medicine, University of Crete, Vassilika Vouton, GR-71110 Heraklion, Greece.
authors.forename: Niki
authors.initials: N
authors.lastname: Tzenaki
authors.forename: Margarita
authors.initials: M
authors.lastname: Andreou
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Stratigi
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Vergetaki
authors.forename: Antonis
authors.initials: A
authors.lastname: Makrigiannakis
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: Evangelia A
authors.initials: EA
authors.lastname: Papakonstanti
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000096:biosynthesis*; D005260:Female; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms; D020033:Protein Isoforms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology
chemical_list: C477872:IC 87114; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D011799:Quinazolines; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000225:Adenine