Rubus idaeus L Inhibits Invasion Potential of Human A549 Lung Cancer Cells by Suppression Epithelial-to-Mesenchymal Transition and Akt Pathway In Vitro and Reduces Tumor Growth In Vivo

• Published in: Integrative cancer therapies Vol. 13; no. 3; pp. 259 - 273
• Main Authors: Chu, Shu-Chen, Hsieh, Yih-Shou, Hsu, Li-Sung, Chen, Kuo-Shuen, Chiang, Chien-Cheng, Chen, Pei-Ni
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.05.2014
• Subjects: Animals; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Cell Line, Tumor; Cell Movement - drug effects; Epithelial-Mesenchymal Transition - drug effects; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness - prevention & control; Neoplasm Metastasis - prevention & control; Plant Extracts - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Rubus - chemistry; Solvents - chemistry; Xenograft Model Antitumor Assays; lung cancer; raspberry; MMP; invasion; u-PA; EMT
• ISSN: 1534-7354; 1552-695X
• DOI: 10.1177/1534735413510559

The metastasis of lung cancer is the most prevalent cause of patient death. Various treatment strategies have targeted the prevention of the occurrence of metastasis. The epithelial–mesenchymal transition (EMT) in lung cancer cells is considered a prerequisite to acquire the invasive/migratory phenotype and to subsequently achieve metastasis. However, the effects of Rubus idaeus on cancer invasion and the EMT of the human lung carcinoma remain unclear. In this article, we test the hypothesis that R idaeus ethyl acetate (RIAE) possesses an antimetastatic effect and reverses the EMT potential of human lung A549 cells. We extract the raspberry R idaeus with methanol (RIME), chloroform (RICE), ethyl acetate (RIAE), n-butanol (RIBE), and water (RIWE). The RIAE treatment obviously inhibits the invasive (P < .001), motility (P < .001), spreading, and migratory potential (P < .001) of highly metastatic human lung cancer A549 cells. The zymography and promoter luciferase analysis reveals that RIAE decreases the proteinase and transcription activities of MMP-2 and u-PA. Molecular analyses show that RIAE increases the E-cadherin level that is mainly localized at the cellular membrane. This result was also verified through confocal analyses. RIAE also induces the upregulation of an epithelial marker, such as α-catenin, and decreases mesenchymal markers, such as snail-1 and N-cadherin, that promote cell invasion and metastasis. RIAE inhibits MMP-2 and u-PA by attenuating the NF-κB and p-Akt expression. The inhibition of RIAE on the growth of A549 cells in vivo was also verified using a cancer cell xenograft nude mice model. Our results show the anti-invasive/antitumor effects of RIAE and associated mechanisms, which suggest that RIAE should be further tested in clinically relevant models to exploit its potential benefits against metastatic lung cancer cells.