Rubus idaeus L. reverses epithelial-to-mesenchymal transition and suppresses cell invasion and protease activities by targeting ERK1/2 and FAK pathways in human lung cancer cells

• Published in: Food and chemical toxicology Vol. 62; pp. 908 - 918
• Main Authors: Hsieh, Yih-Shou, Chu, Shu-Chen, Hsu, Li-Sung, Chen, Kuo-Shuen, Lai, Ming-Tsung, Yeh, Chia-Heng, Chen, Pei-Ni
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.12.2013; Elsevier
• Subjects: Animals; Antineoplastic Agents, Phytogenic - pharmacology; Biological and medical sciences; Cadherins - metabolism; cell invasion; Cell Line, Tumor; Cell Movement - drug effects; EMT; Epithelial-Mesenchymal Transition - drug effects; FAK; fibronectins; Focal Adhesion Kinase 1 - metabolism; gelatinase A; Humans; Invasion; lung neoplasms; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Medical sciences; metastasis; mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; MMP-2; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); neoplasm cells; Plant Extracts - pharmacology; plasminogen activator; Pneumology; Rubus - chemistry; Rubus idaeus; Snail Family Transcription Factors; Toxicology; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors; Tumors of the respiratory system and mediastinum; u-PA; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - metabolism; vimentin; Western blotting; Xenograft Model Antitumor Assays; MMP; FAK; MMP-2; Rubus idaeus; u-PA; EMT; Invasion; RIE; Targeting; Lung cancer; Rosaceae; Activity; Bronchopulmonary; Signal transduction; Target; Dicotyledones; Angiospermae; Bronchus disease; Tumor cell; Human; Lung disease; Enzyme; Respiratory disease; Malignant tumor; Peptidases; Hydrolases; Spermatophyta; Epithelial mesenchymal transition; Cancer; epithelial–mesenchymal transition; focal adhesion kinase; Rubus idaeus L. extracts; matrix metalloproteinase; urokinasetype plasminogen activator
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2013.10.021

•RIE inhibited cell invasion and cell migration in A549 cells.•RIE is able to transcriptionally regulated MMP-2 and u-PA expression.•RIE reversed EMT by modulating E-cadherin and snail-1expression.•RIE reduced the growth of tumor by BALB/c nude mice xenograft model. Epithelial to mesenchymal transition (EMT) has been considered essential for cancer metastasis, a multistep complicated process including local invasion, intravasation, extravasation, and proliferation at distant sites. Herein we provided molecular evidence associated with the antimetastatic effect of Rubus idaeus L. extracts (RIE) by showing a nearly complete inhibition on the invasion (p<0.001) of highly metastatic A549 cells via reduced activities of matrix metalloproteinase-2 (MMP-2) and urokinasetype plasminogen activator (u-PA). We performed Western blot to find that RIE could induce up-regulation of epithelial marker such as E-cadherin and α-catenin and inhibit the mesenchymal markers such as N-cadherin, fibronectin, snail-1, and vimentin. Selective snail-1 inhibition by snail-1-specific-siRNA also showed increased E-cadherin expression in A549 cells suggesting a possible involvement of snail-1 inhibition in RIE-caused increase in E-cadherin level. RIE also inhibited p-FAK, p-paxillin and AP-1 by Western blot analysis, indicating the anti-EMT effect of RIE in human lung carcinoma. Importantly, an in vivo BALB/c nude mice xenograft model showed that RIE treatment reduced tumor growth by oral gavage, and RIE represent promising candidates for future phytochemical-based mechanistic pathway-targeted cancer prevention strategies.