Propolin C Inhibited Migration and Invasion via Suppression of EGFR‐Mediated Epithelial‐to‐Mesenchymal Transition in Human Lung Cancer Cells

Abstract

Controlling lung cancer cell migration and invasion via epithelial-to-mesenchymal transition (EMT) through the regulation of epidermal growth factor receptor (EGFR) signaling pathway has been demonstrated. Searching biological active phytochemicals to repress EGFR-regulated EMT might prevent lung cancer progression. Propolis has been used as folk medicine in many countries and possesses anti-inflammatory, antioxidant, and anticancer activities. In this study, the antimigration and anti-invasion activities of propolin C, a c-prenylflavanone from Taiwanese propolis, were investigated on EGFR-regulated EMT signaling pathway. Cell migration and invasion activities were dose-dependently suppressed by noncytotoxic concentration of propolin C. Downregulations of vimentin and snail as well as upregulation of E-cadherin expressions were through the inhibition of EGFR-mediated phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinase (ERK) signaling pathway in propolin C-treated cells. In addition, EGF-induced migration and invasion were suppressed by propolin C-treated A549 lung cancer cells. No significant differences in E-cadherin expression were observed in EGF-stimulated cells. Interestingly, EGF-induced expressions of vimentin, snail, and slug were suppressed through the inhibition of PI3K/Akt and ERK signaling pathway in propolin C-treated cells. Inhibition of cell migration and invasion by propolin C was through the inhibition of EGF/EGFR-mediated signaling pathway, followed by EMT suppression in lung cancer.

Chemical composition and pharmacological properties of Macaranga‐type Pacific propolis: A review

“…However, NA was also found to be a powerful apoptosis inducer and cell‐cycle inhibitor at the G2/M phase, which functions by activating caspase‐3, caspase‐8, and Bid, and inducing cytochrome c release from the mitochondria into the cytoplasm, thereby showing strong cytotoxic effects on human melanoma cells, with an IC 50 value of 8.5 μM (Chen, Wu, & Lin, 2004). Recently, Pai et al (2018) reported that NA at 10 μM did not affect cell proliferation and cell cycles in epidermal growth factor receptor (EGFR)‐mutated HCC827 cells, whereas it dose‐dependently suppressed cell migration and invasion by downregulating the EGFR/phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (Akt) and extracellular signal‐regulated kinase (ERK)‐mediated epithelial‐to‐mesenchymal transition (EMT) signaling pathways. In addition, NA inhibited epidermal growth factor‐induced migration and invasion, as well as mesenchymal‐like marker expression in EGFR wild‐type A549 lung cancer cells.…”

“…In addition, NA inhibited epidermal growth factor‐induced migration and invasion, as well as mesenchymal‐like marker expression in EGFR wild‐type A549 lung cancer cells. It was, therefore, suggested to be an effective EGFR inhibitor and might become an antitumorigenic candidate compound for lung cancer treatment and/or prevention in the future (Pai et al, 2018). Similarly, NC can suppress fibroblast growth factor 18 (FGF18) by lowering the β‐catenin level in the Wnt/β‐catenin pathway, which can also reduce the phosphorylation level of ERK1/2 in the mitogen‐activated protein kinase cascade.…”

“…They impart anti‐inflammatory effects by reducing the expression of inflammatory cytokines, including TNF‐α, IL‐6, IL‐1β, and MCP‐1, and modulating inflammatory enzymes, such as COX‐2 (Chen, Chien, et al, 2018; Hošek et al, 2010; Hsieh et al, 2019; Shahinozzaman et al, 2018). Moreover, their anticancer mechanisms mainly involve reducing apoptosis‐related proteins (procaspase‐3, procaspase‐8, Bid, DFF45, and PARP), inhibiting cell division kinases (CDK2 and CDK4), and modulating several signaling cascades, including the Wnt/β‐catenin, EGFR/PI3K/Akt, and EMT pathways, and other signaling components such as ERK1/2, MEK1/2, and FGF18 (Chen et al, 2007; Chen, Weng, et al, 2004; Chen, Wu, & Lin, 2004; Pai et al, 2018; Weng et al, 2007; Yoshimura et al, 2017).…”

“…Propolis has been effectively used for traditionally treating a variety of inflammatory diseases since the ancient Egyptian era (Maruta, 2013). Chen, Chien, et al (2018) first confirmed that TP extract can significantly decrease the expression of major inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1 beta (IL- OP extract Antioxidant, anti-melanogenic, anticancer, longevity extension Kumazawa et al, 2008;Taira et al, 2016 TP extract Antioxidant, antimicrobial, antiinflammation, antidiabetic, Antifibrotic, cytotoxic, apoptosis induction Chen, Weng, et al, 2004;Chen et al, 2019;Chen, Chien, et al, 2018;Chen et al, 2008;Chen, Ye, et al, 2018;Hsieh et al, 2019;Huang et al, 2007;Lu et al, 2003Lu et al, , 2005Su et al, 2014 Nymphaeol-A Antioxidant, antimicrobial, antiinflammatory, anticancer, antidiabetic, anti-Alzheimer's, apoptosis induction Chen, Ye, et al, 2018;Kumazawa et al, 2004Kumazawa et al, , 2007Lee et al, 2019;Massaro et al, 2015;Nguyen, Yoshimura, Kumazawa, Tawata, & Maruta, 2017;Pai et al, 2018;Raghukumar et al, 2010;Shahinozzaman et al, 2018 Nymphaeol-B Antioxidant, antimicrobial, antiinflammatory, anticancer, antidiabetic, anti-Alzheimer's, antiaging Chen, Ye, et al, 2018;Kumazawa et al, 2004Kumazawa et al, , 2007Lee et al, 2019;Raghukumar et al, 2010;Shahinozzaman et al, 2018;Taira et al, 2016 Nymphaeol-C Antioxidant, antimicrobial, antiinflammatory, anticancer, antidiabetic, anti-Alzheimer's, Antifibrotic, Neuroprotective, apoptosis induction Chen, Ye, et al, 2018;…”

“…In contrast, TP extract has been widely used in traditional medicine in Taiwan (Chen, Chien, et al, 2018) and has been more thoroughly investigated to date. It has been found to have many health benefits, including antioxidant, anti‐inflammation, antimicrobial, anticancer, antidiabetic, and liver protection benefits, together with exploring specific mechanisms and molecular targets, especially for its action against inflammation and cancer (Chen, Wu, Shy, & Lin, 2003; Chen, Weng, et al, 2004; Chen, Wu, & Lin, 2004, 2007; Chen et al, 2012; Chen, Chien, Yu, & Chen, 2019; Chen, Chien, et al, 2018; Chen et al, 2008; Chen, Ye, Ting, & Yu, 2018; Hsieh et al, 2019; Huang et al, 2007, 2011, 2012; Lu et al, 2003, 2005; Pai, Lee, Chen, Leu, & Weng, 2018; Popova, Chen, Chen, Huang, & Bankova, 2009; Su et al, 2014; Suk et al, 2013; Weng, Liao, Chen, Wu, & Lin, 2007). Although HP is a Macaranga ‐type propolis, only its chemical composition has been studied so far (Inui, Hosoya, & Kumazawa, 2014).…”