Luteolin reduces the invasive potential of malignant melanoma cells by targeting β3 integrin and the epithelial-mesenchymal transition

Abstract

Aim: To investigate whether luteolin, a highly prevalent flavonoid, reverses the effects of epithelial-mesenchymal transition (EMT) in vitro and in vivo and to determine the mechanisms underlying this reversal. Methods: Murine malignant melanoma B16F10 cells were exposed to 1% O 2 for 24 h. Cellular mobility and adhesion were assessed using Boyden chamber transwell assay and cell adhesion assay, respectively. EMT-related proteins, such as E-cadherin and N-cadherin, were examined using Western blotting. Female C57BL/6 mice (6 to 8 weeks old) were injected with B16F10 cells (1×10 6 cells in 0.2 mL per mouse) via the lateral tail vein. The mice were treated with luteolin (10 or 20 mg/kg, ip) daily for 23 d. On the 23rd day after tumor injection, the mice were sacrificed, and the lungs were collected, and metastatic foci in the lung surfaces were photographed. Tissue sections were analyzed with immunohistochemistry and HE staining. Results: Hypoxia changed the morphology of B16F10 cells in vitro from the cobblestone-like to mesenchymal-like strips, which was accompanied by increased cellular adhesion and invasion. Luteolin (5−50 µmol/L) suppressed the hypoxia-induced changes in the cells in a dose-dependent manner. Hypoxia significantly decreased the expression of E-cadherin while increased the expression of N-cadherin in the cells (indicating the occurrence of EMT-like transformation), which was reversed by luteolin (5 μmol/L). In B16F10 cells, luteolin up-regulated E-cadherin at least partly via inhibiting the β3 integrin/FAK signal pathway. In experimental metastasis model mice, treatment with luteolin (10 or 20 mg/kg) reduced metastatic colonization in the lungs by 50%. Furthermore, the treatment increased the expression of E-cadherin while reduced the expression of vimentin and β3 integrin in the tumor tissues. Conclusion: Luteolin inhibits the hypoxia-induced EMT in malignant melanoma cells both in vitro and in vivo via the regulation of β3 integrin, suggesting that luteolin may be applied as a potential anticancer chemopreventative and chemotherapeutic agent.

Luteolin, a Bioflavonoid Inhibits Colorectal Cancer through Modulation of Multiple Signaling Pathways: A Review

“…Because food derived products exist universally and are expected to be safe, they are highly interesting for development as chemopreventive agents to treat cancer (Sengupta et al, 2002;Chihara et al, 2010). Luteolin act as a strong anticancer agent against many types of malignancies including liver, lung, breast, esophageal squamous carcinoma, colon, prostate and melanoma (Zhou et al, 2009;Hwang et al, 2011;Tang et al, 2011;Wang et al, 2012a;Wang et al, 2012b;Ruan et al, 2012;Pandurangan et al, 2014a). This review is aimed to emphasize the molecular action of luteolin on molecular targets of colorectal cancer.…”

Luteolin Arrests Cell Cycling, Induces Apoptosis and Inhibits the JAK/STAT3 Pathway in Human Cholangiocarcinoma Cells

“…Luteolin has been shown to be beneficial to human health due to its strong antioxidant, radical scavenging and anti-inflammatory properties (LopezLazaro, 2009). Moreover, there are several reports about the anticancer properties of luteolin including induction of cancer cell apoptosis and cell cycle arrest (Wang et al, 2012), and inhibition of cancer cell invasiveness (Ruan et al, 2012) and angiogenesis (Pratheeshkumar et al, 2012). Despite several studies elucidating significant anticancer activity of luteolin against various cancers (Wang et al, 2012;George et al, 2013), its activity against CCA remains to be addressed.…”

Phytochemicals for the Management of Melanoma

“…It has been found to inhibit angiogenesis, promote apoptosis, and sensitize cells to anti-cancer therapy in a variety of malignancies [342]. The compound was found to induce melanogenesis and reduce invasive potential of B16F10 melanoma cells by decreasing EMT through inhibition of the β3 integrin/FAK signal pathway [343–345]. Luteolin protected DNA, inhibited cell cycle progression and promoted apoptosis in A375 melanoma cells in a different investigation [346–348].…”