Targeting p21-activated kinase 1 inhibits growth and metastasis via Raf1/MEK1/ERK signaling in esophageal squamous cell carcinoma cells
Targeting p21-activated kinase 1 inhibits growth and metastasis via Raf1/MEK1/ERK signaling in esophageal squamous cell carcinoma cells
复制标题
靶向 p21 激活激酶 1 通过 Raf1/MEK1/ERK 信号传导抑制食管鳞状细胞癌细胞的生长和转移
DOI：
10.1186/s12964-019-0343-5
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发表时间：
2019-04-11
影响因子：
8.4
通讯作者：
Xie, Songqiang
中科院分区：
文献类型：
--
作者：
Chen, Liang;Bi, Shuning;Xie, Songqiang
背景 p21 激活激酶 1 (PAK1) 在促进多种癌症的发生和进展中发挥着基础作用，是潜在的治疗靶点。然而，PAK1在食管鳞状细胞癌（ESCC）中的生物学功能和潜在机制仍不清楚。方法检测食管鳞状细胞癌细胞系和临床样本中PAK1的表达。通过MTT、焦点形成和软琼脂测定来测量细胞生长。通过伤口愈合和transwell实验检测细胞迁移和侵袭。通过皮下致瘤和尾静脉转移的动物模型来测定药理学抑制剂IPA-3对ESCC细胞肿瘤生长和转移的抑制作用。结果我们发现PAK1在ESCC中频繁过度表达。 PAK1 的异位表达促进细胞生长、集落形成和贴壁依赖性生长。过表达PAK1还增强ESCC细胞中的迁移、侵袭以及MMP-2和MMP-9的表达。相反，通过慢病毒敲低或特异性抑制剂IPA-3沉默PAK1会产生相反的效果。随后的研究表明Raf1/MEK1/ERK信号通路参与了PAK1介导的作用。 Raf1 表达的增强减弱了 PAK1 shRNA 的抑制功能。而 shRNA 阻断 Raf1 或 U0126 特异性抑制 MEK1 可拮抗 PAK1 对 ESCC 细胞的致癌作用。更重要的是，IPA-3对PAK1的药理学抑制显着抑制体内ESCC细胞的肿瘤生长和肺转移。结论这些数据支持PAK1是开发针对转移性ESCC患者的潜在治疗药物的理想靶点。
Backgroundp21-activated kinase 1 (PAK1) plays a fundamental role in promoting the development and progression of several cancers and is a potential therapeutic target. However, the biological function and underlying mechanism of PAK1 in esophageal squamous cell carcinoma (ESCC) remain unclear.MethodsThe expression of PAK1 was detected in both ESCC cell lines and clinical samples. Cell growth was measured by MTT, focus formation and soft agar assays. Cell migration and invasion were detected by wound healing and transwell assays. Animal models of subcutaneous tumourigenicity and tail vein metastasis were performed to determine the inhibitory effect of pharmacological inhibitor IPA-3 on tumor growth and metastasis of ESCC cells.ResultsWe found that PAK1 was frequently overexpressed in ESCC. Ectopic expression of PAK1 promoted cellular growth, colony formation and anchorage-independent growth. Overexpressing PAK1 also enhanced migration, invasion and the expression of MMP-2 and MMP-9 in ESCC cells. In contrast, silencing PAK1 by lentiviral knockdown or a specific inhibitor IPA-3 resulted in a contrary effect. Subsequent investigations revealed that Raf1/MEK1/ERK signaling pathway was involved in PAK1-mediated effect. Enhanced expression of Raf1 attenuated the inhibitory functions of PAK1 shRNA. Whereas blocking of Raf1 by shRNA or specific inhibition of MEK1 by U0126 antagonized the oncogenetic effect of PAK1 on ESCC cells. More importantly, Pharmacological inhibition of PAK1 by IPA-3 significantly suppressed tumor growth and lung metastasis of ESCC cells in vivo.ConclusionsThese data support that PAK1 is an ideal target for the development of potential therapeutic drugs for ESCC patients even with metastasis.