橙皮苷通过靶向 circ_0007503 并抑制 PI3K/Akt 通路抑制乳腺癌发生。

Eriodictyol inhibits breast carcinogenesis by targeting circ_0007503 and repressing PI3K/Akt pathway.

机构信息

College of Food Science, Southwest University, No.2 Tiansheng Road, BeiBei District, Chongqing 400715, China.

出版信息

Phytomedicine. 2022 Jul 20;102:154159. doi: 10.1016/j.phymed.2022.154159. Epub 2022 May 7.

DOI:10.1016/j.phymed.2022.154159

PMID:35580441

Abstract

BACKGROUND

Eriodictyol in citrus fruits, Eriodictyon californicum and several Chinese herbal medicines shows great promise for chronic disease prevention, including cancers. However, its role in chemopreventive activities against breast carcinogenesis is unknown.

PURPOSE

In the present study, we investigated the chemopreventive effect and the underlying mechanism of eriodictyol on carcinogens-induced breast carcinogenesis in vivo and in vitro.

METHODS

The carcinogenic transformation in MCF10A cells was induced by the environmental carcinogens in vitro. The chemopreventive effect in vivo was evaluated by using the experimental model of 1-methyl-1-nitrosourea (MNU)-induced mammary tumorigenesis in rats. The activation of the PI3K/Akt pathway was detected by western blot assay; the levels of circular RNAs (circRNAs) were measured by qRT-PCR.

RESULTS

First, eriodictyol significantly reduces cells viability and induces apoptosis in breast cancer cells in a dose-dependent manner in vitro (P < 0.05). Next, eriodictyol could effectively suppress environmental carcinogens-induced acquisition of carcinogenic properties in human breast epithelial cell MCF10A (P < 0.05). In vivo, eriodictyol administration reduces the incidence of mammary tumor by 50% in carcinogen-treated female rats (P < 0.05). Further study revealed that eriodictyol represses the PI3K/Akt signaling pathway and down-regulates the level of circ_0007503 in breast cancer cells and in breast carcinogenesis (P < 0.01). When the effect of eriodictyol on circ_0007503 was blocked by transfection of a circ_0007503 over-expression plasmid, the cytotoxic effects and the suppression of the PI3K/Akt pathway of eriodictyol in breast cancer cells were significantly reduced (P < 0.05).

CONCLUSION

Our data indicated that eriodictyol could effectively suppress breast carcinogenesis in vitro and in vivoThe mechanism may be attributed to targeting circ_0007503 and inhibiting PI3K/Akt pathway.

摘要

背景

柑橘类水果、加利福尼亚鼠尾草和几种中草药中的橙皮苷在预防慢性病方面显示出巨大的潜力，包括癌症。然而，其在预防乳腺癌发生中的作用尚不清楚。

目的

本研究旨在探讨橙皮苷在体内和体外对环境致癌物诱导的乳腺癌发生的化学预防作用及其作用机制。

方法

体外采用环境致癌物诱导 MCF10A 细胞癌变，体内采用 1-甲基-1-亚硝脲（MNU）诱导的大鼠乳腺肿瘤发生模型评价化学预防作用。用 Western blot 检测 PI3K/Akt 通路的激活情况；用 qRT-PCR 检测环状 RNA（circRNA）的水平。

结果

首先，橙皮苷在体外呈剂量依赖性显著降低乳腺癌细胞的活力并诱导其凋亡（P<0.05）。其次，橙皮苷可有效抑制环境致癌物诱导的人乳腺上皮细胞 MCF10A 获得致癌特性（P<0.05）。体内，橙皮苷给药可使致癌物处理的雌性大鼠乳腺肿瘤的发生率降低 50%（P<0.05）。进一步研究表明，橙皮苷抑制 PI3K/Akt 信号通路，并下调乳腺癌细胞和乳腺癌发生中 circ_0007503 的水平（P<0.01）。当用 circ_0007503 过表达质粒转染阻断橙皮苷对 circ_0007503 的作用时，橙皮苷对乳腺癌细胞的细胞毒性作用和对 PI3K/Akt 通路的抑制作用明显降低（P<0.05）。