Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma.
Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma.
复制标题
DOI：
10.1158/1078-0432.ccr-08-0170
复制
发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Walker CL
中科院分区：
文献类型：
--
作者：
Kim J;Jonasch E;Alexander A;Short JD;Cai S;Wen S;Tsavachidou D;Tamboli P;Czerniak BA;Do KA;Wu KJ;Marlow LA;Wood CG;Copland JA;Walker CL
p27的定位和表达对肿瘤的预后有一定的预测价值。关于p27在肾细胞癌（RCC）中的表达模式，或p27如何参与疾病进展或对治疗的反应，知之甚少。分析RCC衍生的细胞系、原发性肿瘤和正常肾上皮细胞的p27表达、磷酸化（NLS的T157）和亚细胞定位。用PI 3 K和mTOR抑制剂处理RCC衍生的细胞系，并评估对p27定位的影响。还评估了细胞质p27对细胞凋亡抗性的潜在贡献。与对照组相比，p27在肿瘤中升高，并且p27的细胞质错误定位与肿瘤分级增加相关。p27的胞质定位与T157的磷酸化相关，T157是p27 NLS中的AKT磷酸化位点。在RCC细胞系中，激活的PI 3 K/AKT信号伴随着p27的错误定位。AKT激活和p27磷酸化与细胞凋亡抗性相关，siRNA敲低p27或重新定位到细胞核增加了RCC细胞的凋亡。用PI 3 K抑制剂LY 294002或渥曼青霉素处理导致p27的核重定位，而雷帕霉素抑制mTOR则没有。在RCC中，p27在NLS的T157处磷酸化，随着与细胞质p27相关的肿瘤分级的增加。PI 3 K抑制（其降低AKT活性）降低T157磷酸化并诱导p27的核再定位，而mTOR抑制则不会。这些发现的临床测试可能为RCC患者使用mTOR和PI 3 K/AKT通路抑制剂提供合理的方法。
p27 localization and expression has prognostic and predictive value in cancer. Little is known regarding expression patterns of p27 in renal cell carcinoma (RCC), or how p27 participates in disease progression or response to therapy. RCC-derived cell lines, primary tumors and normal renal epithelial cells were analyzed for p27 expression, phosphorylation (T157 of the NLS) and subcellular localization. RCC-derived cell lines were treated with PI3K and mTOR inhibitors and effects on p27 localization assessed. The potential contribution of cytoplasmic p27 to resistance to apoptosis was also evaluated. p27 was elevated in tumors compared with matched controls, and cytoplasmic mislocalization of p27 was associated with increasing tumor grade. Cytoplasmic localization of p27 correlated with phosphorylation at T157, an AKT phosphorylation site in the p27 NLS. In RCC cell lines, activated PI3K/AKT signaling was accompanied by mislocalization of p27. AKT activation and phosphorylation of p27 was associated with resistance to apoptosis, and siRNA knockdown of p27 or relocalization to the nucleus increased apoptosis in RCC cells. Treatment with the PI3K inhibitors LY294002 or wortmannin resulted in nuclear relocalization of p27, whereas mTOR inhibition by rapamycin did not. In RCC, p27 is phosphorylated at T157 of the NLS, with increasing tumor grade associated with cytoplasmic p27. PI3K inhibition (which reduces AKT activity) reduces T157 phosphorylation and induces nuclear relocalization of p27 whereas mTOR inhibition does not. Clinical testing of these findings may provide a rational approach for use of mTOR and PI3K/AKT pathway inhibitors in patients with RCC.