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

Oncogene volume 31, pages 2350–2361 (2012)Cite this article

Abstract

Phosphoinositide 3-kinase γ (PI3Kγ) consists of a catalytic subunit p110γ, which forms mutually exclusive dimers with one of the regulatory subunits called p101 and p84/p87PIKAP. Recently, PI3Kγ emerged as being a potential oncogene because overexpression of the catalytic subunit p110γ 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 PI3Kγ subunits (p84, p101 and p110γ) in MDA-MB-231 cells, which reduced in vitro migration of the cell lines. Knockdown of p110γ or p101 inhibited apoptosis, Akt phosphorylation and lung colonization in SCID mice. Similarly, the knockdown of p110γ 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 PI3Kγ 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 p110γ.

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Acknowledgements

We thank Mark Bunting for assistance with animal experiments, John Brazzatti for assistance with statistical analysis and Francisco Olmo for assistance with apoptosis experiments. The work was supported by grants from the National Health and Medical Research Council of Australia.

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  1. S Haylock-Jacobs

    Present address: 2Current address: Department of Clinical Neurosciences, University of Calgary, 191 HMRB, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.,

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  1. School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia

    J A Brazzatti, M Klingler-Hoffmann, S Haylock-Jacobs, Y Harata-Lee, M Niu, M D Higgins, M Kochetkova, P Hoffmann & S R McColl

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Brazzatti, J., Klingler-Hoffmann, M., Haylock-Jacobs, S. et al. Differential roles for the p101 and p84 regulatory subunits of PI3Kγ in tumor growth and metastasis. Oncogene 31, 2350–2361 (2012). https://doi.org/10.1038/onc.2011.414

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