Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)K gamma

Phosphoinositide-3-OH kinases (PI(3)Ks) constitute a family of evolutionari ly conserved lipid kinases that regulate a vast array of fundamental cellul ar responses, including proliferation, transformation, differentiation and protection from apoptosis(1,2). PI(3)K-mediated activation of the cell surv ival kinase PKB/Akt, and negative regulation of PI(3)K signalling by the tu mour suppressor PTEN (refs 3, 4) are key regulatory events in tumorigenesis (5-7). Thus, a model has arisen that PI(3)K gamma promote development of ca ncers. Here we report that genetic inactivation of the p110 gamma catalytic subunit of PI(3)K gamma (ref. 8) leads to development of invasive colorect al adenocarcinomas in mice. In humans, p110 gamma protein expression is los t in primary colorectal adenocarcinomas from patients and in colon cancer c ell lines. Overexpression of wild-type or kinase-dead p110 gamma in human c olon cancer cells with mutations of the tumour suppressors APC and p53, or the oncogenes beta-catenin and Ki-ras, suppressed tumorigenesis. Thus, loss of p110 gamma in mice leads to spontaneous, malignant epithelial tumours i n the colorectum and p110 gamma can block the growth of human colon cancer cells.