虽然去势治疗通常能有效降低前列腺癌的病情，但晚期难治性去势抵抗性前列腺癌（CRPC）最终会发生。了解CRPC的转移进展是非常重要的，但目前尚未明确定义。PTEN的丢失，在PI3K通路中的磷酸酯酶去磷酸化磷脂酰肌醇3,4,5-三磷酸（PIP3）上发生的比例高达70%至80%。我们从C57BL/6背景的PTEN基因敲除和Hi-Myc转基因小鼠中，产生了一个雄激素非依赖的前列腺癌细胞系（PKO）。我们确认了该PKO细胞系激活了PI3K通路，并能在裸鼠和C57BL/6免疫完整小鼠的股骨和胫骨处发生转移。我们发现在体外实验证实，去势能显著增强PKO细胞的迁移和侵袭能力，该过程通过p110β依赖的PAK1-MAPK激活进行。抑制p110β-PAK1轴可显著降低前列腺癌细胞的迁移和侵袭。值得注意的是，我们对临床样本的分析显示，在CRPC中PAK1的活化程度高于晚期前列腺癌；高水平的PAK1/磷酸化-PAK1与CRPC患者的生存率降低相关。所有的信息表明这一细胞系反映了CRPC细胞的特性，并可用于解析CRPC发生和发展的机制。这项研究也显示PAK1是CRPC治疗的潜在靶点。意义：本研究使用新生成的PTEN基因敲除前列腺癌细胞系，定义了p110β-PAK1在CRPC迁移和侵袭中的关键功能。本研究还表明，p110β-PAK1轴可能成为CRPC转移的治疗靶点。

Although androgen deprivation treatment often effectively decreases prostate cancer, incurable metastatic castration-resistant prostate cancer (CRPC) eventually occurs. It is important to understand how CRPC metastasis progresses, which is not clearly defined. The loss of PTEN, a phosphatase to dephosphorylate phosphatidylinositol 3,4,5-trisphosphate in the PI3K pathway, occurs in up to 70~80% of CRPC. We generated a mouse androgen-independent prostate cancer cell line (PKO) from PTEN null and Hi-Myc transgenic mice in C57BL/6 background. We confirmed that this PKO cell line has an activated PI3K pathway and can metastasize into the femur and tibia of immunodeficient nude and immunocompetent C57BL/6 mice. In vitro, we found that androgen deprivation significantly enhanced PKO cell migration/invasion via the p110β isoform-depended PAK1-MAPK activation. Inhibition of the p110β-PAK1 axis significantly decreased prostate cancer cell migration/invasion. Of note, our analysis using clinical samples showed that PAK1 is more activated in CRPC than in advanced prostate cancer; high PAK1/phosphorylated-PAK1 levels are associated with decreased survival rates in CRPC patients. All the information suggests that this cell line reflects the characteristics of CRPC cells and can be applied to dissect the mechanism of CRPC initiation and progression. This study also shows that PAK1 is a potential target for CRPC treatment. Implications: This study uses a newly generated PTEN null prostate cancer cell line to define a critical functional role of p110β-PAK1 in CRPC migration/invasion. This study also shows that the p110β-PAK1 axis can potentially be a therapeutic target in CRPC metastasis.