School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
Oncogene. 2012 May 3;31(18):2350-61. doi: 10.1038/onc.2011.414. Epub 2011 Sep 26.
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/p87(PIKAP). 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.
磷酸肌醇 3-激酶 γ（PI3Kγ）由一个催化亚基 p110γ 组成，它与一个称为 p101 和 p84/p87（PIKAP）的调节亚基形成互斥二聚体。最近，PI3Kγ 作为一种潜在的致癌基因出现，因为催化亚基 p110γ 或调节亚基 p101 的过度表达导致致癌细胞转化和恶性肿瘤。然而，各个亚基对肿瘤生长和转移的贡献以及涉及的机制尚不清楚。因此，我们在 MDA-MB-231 细胞中分别敲低了 PI3Kγ 亚基（p84、p101 和 p110γ），这降低了细胞系的体外迁移。敲低 p110γ 或 p101 抑制了 SCID 小鼠中的细胞凋亡、Akt 磷酸化和肺定植。类似地，在小鼠上皮癌 4T1.2 细胞中敲低 p110γ 和 p101 抑制了原发肿瘤生长和自发转移以及肺定植。相比之下，敲低 MDA-MB-231 细胞中的 p84 增强了 Akt 磷酸化和肺定植。这些发现首次表明两个 PI3Kγ 调节亚基在致癌过程中具有不同的功能，并表明 p101 的缺失足以降低体内肿瘤生长和转移的程度与 p110γ 相同。
