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

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dc.contributor.authorBrazzatti, J.
dc.contributor.authorKlingler-Hoffmann, M.
dc.contributor.authorHaylock-Jacobs, S.
dc.contributor.authorHarata-Lee, Y.
dc.contributor.authorNiu, M.
dc.contributor.authorHiggins, M.
dc.contributor.authorKochetkova, M.
dc.contributor.authorHoffmann, P.
dc.contributor.authorMcColl, S.
dc.date.issued2012
dc.description.abstractPhosphoinositide 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.
dc.description.statementofresponsibilityJA Brazzatti, M Klingler-Hoffmann, S Haylock-Jacobs, Y Harata-Lee, M Niu, MD Higgins, M Kochetkova, P Hoffmann and SR McColl
dc.identifier.citationOncogene, 2012; 31(18):2350-2361
dc.identifier.doi10.1038/onc.2011.414
dc.identifier.issn0950-9232
dc.identifier.issn1476-5594
dc.identifier.orcidKlingler-Hoffmann, M. [0000-0003-2165-7813]
dc.identifier.orcidMcColl, S. [0000-0003-0949-4660]
dc.identifier.urihttp://hdl.handle.net/2440/71338
dc.language.isoen
dc.publisherNature Publishing Group
dc.rights© 2012 Macmillan Publishers Limited; All rights reserved
dc.source.urihttps://doi.org/10.1038/onc.2011.414
dc.subjectphosphoinositide 3-kinase γ
dc.subjectp101
dc.subjectp84/p87PIKAP
dc.subjectbreast cancer
dc.subjectapoptosis
dc.titleDifferential roles for the p101 and p84 regulatory subunits of PI3Kγ in tumor growth and metastasis
dc.title.alternativeDifferential roles for the p101 and p84 regulatory subunits of PI3Kgamma in tumor growth and metastasis
dc.typeJournal article
pubs.publication-statusPublished

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