Differential roles for the p101 and p84 regulatory subunits of PI3Kγ in tumor growth and metastasis

Phosphoinositide 3-kinase gamma (PI3K gamma) consists of a catalytic subunit p110 gamma, which forms mutually exclusive dimers with one of the regulatory subunits called p101 and p84/p87(PIKAP). Recently, PI3K gamma emerged as being a potential oncogene because overexpression of the catalytic subunit p110 gamma or the regulatory subunit p101 leads to oncogenic cellular transformation and malignancy. However, the contribution of the individual subunits to tumor growth and metastasis and the mechanisms involved are not understood. We therefore individually knocked down the PI3K gamma subunits (p84, p101 and p110 gamma) in MDA-MB-231 cells, which reduced in vitro migration of the cell lines. Knockdown of p110 gamma or p101 inhibited apoptosis, Akt phosphorylation and lung colonization in SCID mice. Similarly, the knockdown of p110 gamma and p101 in murine epithelial carcinoma 4T1.2 cells inhibited primary tumor growth and spontaneous metastasis, as well as lung colonization. In contrast, knockdown of p84 in MDA-MB-231 cells enhanced Akt phosphorylation and lung colonization. These findings are the first to implicate differential functions of the two PI3K gamma regulatory subunits in the process of oncogenesis, and indicate that loss of p101 is sufficient to reduce in vivo tumor growth and metastasis to the same extent as that of p110 gamma. Oncogene (2012) 31, 2350-2361; doi:10.1038/onc.2011.414; published online 26 September 2011