p110 delta P13 kinase pathway: emerging roles in cancer

Class IA PI3Ks consists of three isoforms of the p110 catalytic subunit designated p1100 alpha, p110[3, and p110 delta which are encoded by three separate genes. Gain-of-function mutations on PIK3CA gene encoding for p110 isoform have been detected in a wide variety of human cancers whereas no somatic mutations of genes encoding for p110 beta or p110 delta have been reported. Unlike p110 and p110 beta which are ubiquitously expressed, p110 delta is highly enriched in leukocytes and thus the p110 delta P13K pathway has attracted more attention for its involvement in immune disorders. However, findings have been accumulated showing that the p110 delta P13K plays a seminal role in the development and progression of some hematologic malignancies. A wealth of knowledge has come from studies showing the central role of p110 delta P13K in B-cell functions and B-cell malignancies. Further data have documented that wild-type p110 delta becomes oncogenic when overexpressed in cell culture models and that p110 delta is the predominant isoform expressed in some human solid tumor cells playing a prominent role in these cells. Genetic inactivation of p110 delta in mice models and highly-selective inhibitors of 0106 have demonstrated an important role of this isoform in differentiation, growth, survival, motility, and morphology with the inositol phosphatase PTEN to play a critical role in p110 delta signaling. In this review, we summarize our understanding of the p110 delta P13K signaling pathway in hematopoietic cells and malignancies, we highlight the evidence showing the oncogenic potential of p110 delta in cells of non-hematopoietic origin and we discuss perspectives for potential novel roles of p110 delta P13K in cancer.