Background

Epidermal growth factor receptor (EGFR) is upregulated in prostate cancer (PCa). However, suppression of EGFR did not improve the patient outcome, possibly due to the activation of PI3K/Akt signaling in PCa. Compounds able to suppress both PI3K/Akt and EGFR signaling may be effective for treating advanced PCa.

Purpose

We examined if caffeic acid phenethyl ester (CAPE) simultaneously suppresses the EGFR and Akt signaling, migration and tumor growth in PCa cells.

Methods

Wound healing assay, transwell migration assay and xenograft mice model were used to determine the effects of CAPE on migration and proliferation of PCa cells. Western blot, immunoprecipitation, and immunohistochemistry staining were performed to determine the effects of CAPE on EGFR and Akt signaling.

Results

CAPE treatment decreased the gene expression of HRAS, RAF1, AKT2, GSK3A, and EGF and the protein expression of phospho-EGFR (Y845, Y1069, Y1148, Y1173), phospho-FAK, Akt, and ERK1/2 in PCa cells. CAPE treatment inhibited the EGF-induced migration of PCa cells. Combined treatment of CAPE with EGFR inhibitor gefitinib showed additive inhibition on migration and proliferation of PCa cells. Injection of CAPE (15 mg/kg/3 days) for 14 days suppressed the tumor growth of prostate xenografts in nude mice as well as suppressed the levels of Ki67, phospho-EGFR Y845, MMP-9, phospho-Akt S473, phospho-Akt T308, Ras, and Raf-1 in prostate xenografts.

Conclusions

Our study suggested that CAPE can simultaneously suppress the EGFR and Akt signaling in PCa cells and is a potential therapeutic agent for advanced PCa.

中文翻译：

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咖啡酸苯乙酯抑制前列腺癌细胞的 EGFR/FAK/Akt 信号、迁移和肿瘤生长

背景

表皮生长因子受体 (EGFR) 在前列腺癌 (PCa) 中上调。然而，抑制 EGFR 并没有改善患者的预后，这可能是由于 PCa 中 PI3K/Akt 信号的激活。能够抑制 PI3K/Akt 和 EGFR 信号的化合物可能对治疗晚期 PCa 有效。

目的

我们检查了咖啡酸苯乙酯 (CAPE) 是否同时抑制 PCa 细胞中的 EGFR 和 Akt 信号传导、迁移和肿瘤生长。

方法

伤口愈合试验、transwell 迁移试验和异种移植小鼠模型用于确定 CAPE 对 PCa 细胞迁移和增殖的影响。进行蛋白质印迹、免疫沉淀和免疫组织化学染色以确定 CAPE 对 EGFR 和 Akt 信号传导的影响。

结果

CAPE 处理降低了 PCa 细胞中HRAS、RAF1、AKT2、GSK3A和EGF的基因表达以及磷酸化 EGFR（Y845、Y1069、Y1148、Y1173）、磷酸化 FAK、Akt 和 ERK1/2 的蛋白表达。CAPE 处理抑制了 EGF 诱导的 PCa 细胞迁移。CAPE 与 EGFR 抑制剂吉非替尼联合治疗显示出对 PCa 细胞迁移和增殖的加性抑制。注射 CAPE（15 mg/kg/3 天）14 天可抑制裸鼠前列腺异种移植物的肿瘤生长，并抑制 Ki67、磷酸-EGFR Y845、MMP-9、磷酸-Akt S473、磷酸-前列腺异种移植物中的 Akt T308、Ras 和 Raf-1。

结论

我们的研究表明，CAPE 可以同时抑制 PCa 细胞中的 EGFR 和 Akt 信号传导，是晚期 PCa 的潜在治疗剂。