PP2A通过Akt/Skp2通路调控p27~(Kip1)的表达并抑制肺癌细胞的致瘤能力

蛋白磷酸酶2A(PP2A)是由36 k Da的催化亚基C(PP2Ac)和65 k Da的结构亚基A(PP2Aα/β)一起组成PP2A的核心酶,并且和各种不同的调节亚基B形成具有不同功能的PP2A全酶复合体。在细胞中PP2A发挥着重要作用,特别是在抑制肿瘤的形成当中,编码PP2Aα/β基因的突变将导致肿瘤的形成和其他疾病。当非小细胞肺癌细胞H1299中过表达PP2A-Aα时,细胞生长被抑制,细胞周期停留在G0/G1期,致瘤能力也同时被抑制。进一步研究证明当PP2A-Aα过表达时,Akt被去磷酸化失活使Skp2的表达下调,从而导致细胞周期抑制因子p27kip1的表达上调。肿瘤细胞软琼脂克隆形成实验的结果表明过表达PP2A-Aα之后H1299细胞的锚定非依赖性生长能力明显的降低,形成的克隆细胞团也较小,这些结果和裸鼠成瘤实验的结果是一致的。

Protein Phosphatase 2A Regulates p27 kip1 Expression and Tumorigenic Capacity of Lung Cancer Cells via Akt/Skp2 Pathway

Protein phosphatase 2A (PP2A)plays an essential role in many aspects of cellular functions and known as an important tumor suppressor.The 36 kDa catalytic subunit (PP2Ac)interacts with the 65 kDa scaffold subunit (PP2A-α/β)making up the core enzyme,which is associated with a wide variety of B regulatory subunits to form a large number of heterotrimeric PP2A holoenzymes.Mutation of the two genes encoding PP2A-α/βleads to carcinogene-sis and other human diseases.Here,we found that overexpression of PP2A-Aαgene can inhibit cell proliferation and tu-morigenicity of H1299 lung cancer cells,and arrest cell cycle at G0 /G1.Further study determined that PP2A-Aαover-expression inhibited cell proliferation was associated with an increase in the level of cell cycle inhibitor,p27 kip1 ,through reduction of Akt-mediated Skp2 expression.Protein phosphatase 2A (PP2A)inhibited Akt phosphorylation and in-creased p27 kip1 expression,indicating that PP2A is involved in the induction of p27 kip1 via Akt inhibition.Moreover,overexpression of PP2A-Aαreduced soft-agar colony formation and anchorage independent growth ability in H1299 cells. This decreased oncogenic potential of H1299 cells was confirmed in vivo in nude mice.Collectively,our results clearly showed that PP2A may inhibit the cell cycle through induction of p27 kip1 ,and inhibit tumor growth in H1299 Lung canc-er cells.