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

Abstract

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.

Rubus idaeusInhibits Migration and Invasion of Human Nasopharyngeal Carcinoma Cells by Suppression of MMP-2 through Modulation of the ERK1/2 Pathway

“…It is well known that berries contain phytochemicals with various biological properties such as anti-oxidant, anti-inflammatory and anticancer activities. Prior studies have demonstrated that extracts from berries can inhibit the growth of many human tumor cell lines, including those of lung, breast, colon, and prostate cancers (Seeram et al, 2006;Chu et al, 2014). In addition, berry extracts have been shown to stimulate apoptosis of a colon cancer cell line (Seeram et al, 2006), suggesting that these natural products can suppress the process of tumorigenesis via multiple pathways.…”

“…Moreover, we found that a higher concentration of RIE was more effective in suppressing NPC cell migration and invasion, suggesting that consumption of more Rubus idaeus as an adjuvant therapy may offer better efficacy in inhibiting metastasis. RIE has been shown to exhibit weak cytostatic effects on human cells at a concentration below 100 μg/mL (Hsieh et al, 2013;Chu et al, 2014), and thus the experimental concentrations of the extract used in the present study should be feasible in a clinical setting. Moreover, previous studied have shown that gallic acid, epigallocatechin (EGC), and catechin are the active substances in RIE (Hsieh et al, 2013).…”

“…Raspberry or Rubus idaeus L. is a plant that belongs to the Rosaceae family. Recent studies have shown that Rubus idaeus can effectively prevent cancer invasion and reduce the rate of lung cancer growth in mice by inhibiting epithelial-to-mesenchymal transition (Hsieh et al, 2013;Chu et al, 2014). However, the mechanism by which Rubus idaeus inhibits the metastasis of NPC cells and the underlying mechanism remains unclear.…”

Rubus idaeus extract suppresses migration and invasion of human oral cancer by inhibiting MMP-2 through modulation of the Erk1/2 signaling pathway

“…For example, Zhang et al, indicated that black raspberry can inhibit the growth of cervical cancer cells and induce cancer cell apoptosis (Zhang et al, ). Lung cancer‐related studies have shown that raspberry can effectively prevent cancer invasion and reduce the rate of lung‐cancer growth in mice by inhibiting epithelial‐to‐mesenchymal transition (EMT), achieving positive treatment outcomes (Chu et al, ; Hsieh et al, ).…”

Capsaicin protects endothelial cells and macrophage against oxidized low-density lipoprotein-induced injury by direct antioxidant action

“…The blot was subsequently operated with standard procedures and probed with primary and secondary antibodies. Protein expression was detected by chemiluminescence using an Immobilon Western Chemiluminescent HRP Substrate kit [23].…”