Institute of Chemical Biology, College of Pharmacy, Henan University, Kaifeng, 475004, China.
Department of Medicine and Therapeutics, Luohe Medical College, Luohe, 462000, China.
Cell Commun Signal. 2019 Apr 11;17(1):31. doi: 10.1186/s12964-019-0343-5.
p21-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.
The 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.
We 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.
These data support that PAK1 is an ideal target for the development of potential therapeutic drugs for ESCC patients even with metastasis.
p21 激活激酶 1（PAK1）在促进多种癌症的发展和进展方面起着至关重要的作用，是一个有潜力的治疗靶点。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。
检测 ESCC 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。通过划痕愈合和 Transwell 测定来检测细胞迁移和侵袭。进行皮下致瘤性和尾静脉转移的动物模型实验，以确定药理学抑制剂 IPA-3 对 ESCC 细胞肿瘤生长和转移的抑制作用。
我们发现 PAK1 在 ESCC 中经常过表达。PAK1 的异位表达促进了细胞生长、集落形成和锚定非依赖性生长。过表达 PAK1 还增强了 ESCC 细胞的迁移、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 则产生相反的效果。随后的研究表明，Raf1/MEK1/ERK 信号通路参与了 PAK1 介导的效应。Raf1 的增强表达减弱了 PAK1 shRNA 的抑制功能。而通过 shRNA 阻断 Raf1 或通过 U0126 特异性抑制 MEK1 拮抗了 PAK1 对 ESCC 细胞的致癌作用。更重要的是，IPA-3 对 PAK1 的药理学抑制显著抑制了 ESCC 细胞在体内的肿瘤生长和肺转移。
这些数据支持 PAK1 是开发针对 ESCC 患者甚至有转移的潜在治疗药物的理想靶点。
