阿魏酸苯乙酯抑制前列腺癌细胞的 EGFR/FAK/Akt 信号转导、迁移和肿瘤生长。

Caffeic acid phenethyl ester suppresses EGFR/FAK/Akt signaling, migration, and tumor growth of prostate cancer cells.

机构信息

Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan; Immunology Research Center, National Health Research Institutes, Miaoli County 35053, Taiwan.

Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan.

出版信息

Phytomedicine. 2023 Jul 25;116:154860. doi: 10.1016/j.phymed.2023.154860. Epub 2023 May 3.

DOI:10.1016/j.phymed.2023.154860

PMID:37201366

Abstract

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.

摘要

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。能够同时抑制 PI3K/Akt 和 EGFR 信号的化合物可能对治疗晚期 PCa 有效。

目的

我们研究了咖啡酸苯乙酯（CAPE）是否能同时抑制 EGFR 和 Akt 信号、PCa 细胞的迁移和肿瘤生长。

方法

利用划痕愈合实验、Transwell 迁移实验和异种移植小鼠模型来确定 CAPE 对 PCa 细胞迁移和增殖的影响。采用 Western blot、免疫沉淀和免疫组化染色来确定 CAPE 对 EGFR 和 Akt 信号的影响。

结果

CAPE 处理降低了 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 PCa 细胞中 EGF 诱导的迁移。CAPE 与 EGFR 抑制剂吉非替尼联合治疗对 PCa 细胞的迁移和增殖具有相加抑制作用。14 天内，15mg/kg/3 天的 CAPE 注射抑制了裸鼠前列腺异种移植瘤的生长，并抑制了前列腺异种移植瘤中 Ki67、磷酸化 EGFR Y845、MMP-9、磷酸化 Akt S473、磷酸化 Akt T308、Ras 和 Raf-1 的水平。