RGS16 Inhibits Breast Cancer Cell Growth by Mitigating Phosphatidylinositol 3-Kinase Signaling
RGS16 Inhibits Breast Cancer Cell Growth by Mitigating Phosphatidylinositol 3-Kinase Signaling
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DOI：
10.1074/jbc.m109.028407
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发表时间：
2009-08-07
影响因子：
4.8
通讯作者：
Druey, Kirk M.
中科院分区：
文献类型：
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作者：
Liang, Genqing;Bansal, Geetanjali;Druey, Kirk M.
磷脂酰肌醇3-激酶（PI3K）通路的异常活性支持许多肿瘤的生长，包括乳腺、肺和前列腺肿瘤。乳腺癌细胞对包括酪氨酸激酶抑制剂（TKI）在内的靶向化疗的耐药性与持续的PI3K活性有关，这可能部分是由于表皮生长因子（EGF）受体（HER2和HER3）的膜表达增加。最近，我们发现RGS （(G) under bar蛋白信号传导的调节因子）家族的蛋白通过从信号复合物中隔离其p85 α亚基来抑制PI3K受体下游的活性。由于相当比例的乳腺肿瘤具有RGS16突变和RGS16蛋白表达降低，我们研究了RGS16调节PI3K活性与乳腺癌细胞生长之间的联系。MCF7乳腺癌细胞中RGS16过表达抑制egf诱导的增殖和Akt磷酸化，而shrna介导的RGS16缺失增强了细胞生长和对TKI治疗的抗性。暴露于TKI也降低了MCF7和BT474细胞系中RGS16的表达。RGS16结合p85 α的氨基末端SH2和SH2间结构域，抑制其与EGF受体相关适配器蛋白Gab1的相互作用。这些结果表明，一些乳腺肿瘤中RGS16的缺失增强了生长因子诱导的PI3K信号，从而促进HER激活下游的增殖和TKI逃避。
Aberrant activity of the phosphatidylinositol 3-kinase (PI3K) pathway supports growth of many tumors including those of breast, lung, and prostate. Resistance of breast cancer cells to targeted chemotherapies including tyrosine kinase inhibitors (TKI) has been linked to persistent PI3K activity, which may in part be due to increased membrane expression of epidermal growth factor (EGF) receptors (HER2 and HER3). Recently we found that proteins of the RGS (regulator of (G) under bar protein signaling) family suppress PI3K activity downstream of the receptor by sequestering its p85 alpha subunit from signaling complexes. Because a substantial percentage of breast tumors have RGS16 mutations and reduced RGS16 protein expression, we investigated the link between regulation of PI3K activity by RGS16 and breast cancer cell growth. RGS16 overexpression in MCF7 breast cancer cells inhibited EGF-induced proliferation and Akt phosphorylation, whereas shRNA-mediated extinction of RGS16 augmented cell growth and resistance to TKI treatment. Exposure to TKI also reduced RGS16 expression in MCF7 and BT474 cell lines. RGS16 bound the amino-terminal SH2 and inter-SH2 domains of p85 alpha and inhibited its interaction with the EGF receptor-associated adapter protein Gab1. These results suggest that the loss of RGS16 in some breast tumors enhances PI3K signaling elicited by growth factors and thereby promotes proliferation and TKI evasion downstream of HER activation.