Nobiletin inhibits epithelial-mesenchymal transition of human non-small cell lung cancer cells by antagonizing the TGF-β1/Smad3 signaling pathway

Abstract

Abstract. Epithelial-mesenchymal transition (EMT) is a critical cellular process in cancer metastasis, during which epithelial polarized cells become motile mesenchymal cells. Since transforming growth factor-β (TGF-β) is a potent inducer of EMT, blocking of TGF-β/Smad signaling has become a promising cancer therapy. Nobiletin, a polymethoxy flavonoid from Citrus depressa, has been shown to be valuable for cancer treatment, yet the mechanism remains unclear. In the present study, lung adenocarcinoma A549 and H1299 cells were used to evaluate the effect of nobiletin on EMT induced by TGF-β1. Nobiletin successfully inhibited TGF-β1-induced EMT, migration, invasion and adhesion in vitro, accompanied by attenuation of MMP-2, MMP-9, p-Src, p-FAK, p-paxillin, Snail, Slug, Twist and ZEB1 expression. Nobiletin inhibited the transcriptional activity of Smads without changing the phosphorylation status or translocation of Smads induced by TGF-β1. Moreover, Smad3 is requisite in TGF-β1-stimulated EMT. Smad3 overexpression meaningfully impaired the ability of nobiletin to reverse TGF-β1-induced EMT. In vivo, nobiletin prohibited the growth of metastatic nodules in the lungs of nude mice. Moreover, nobiletin inhibited tumor growth and reversed EMT in mice bearing A549-Luc xenografts, as revealed by IVIS imaging and immunohistochemical analysis. Collectively, the data suggest that nobiletin prevents EMT by inactivating TGF-β1/Smad3 signaling.

Scutellaria?barbata D. Don inhibits migration and invasion of colorectal cancer cells via suppression of PI3K/AKT and TGF‑β/Smad signaling pathways

“…EMT is an important phenomenon in the occurrence and development of tumors and is also an important mechanism allowing tumor invasion and metastasis (57,58). E-cadherin and N-cadherin are two important factors in the maintenance of the EMT balance; EMT regulation is influenced by these two cadherins (17).…”

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

“…Galunisertib is now in ongoing clinical trials in patients with glioblastoma, pancreatic cancer, and hepatocellular carcinoma . Nobiletin is a flavonoid compound isolated from Citrus depressa that suppressed EMT by antagonizing the TGF‐β1/Smad signaling pathway in human non–small‐cell lung cancer cells . In addition, oridonin is a diterpenoid from Rabdosia rubescens (Hemsl.)…”

Chemopreventive Agents and Inhibitors of Cancer Hallmarks: May Citrus Offer New Perspectives?

“…Moreover, nobiletin has been shown to reduce adhesion, invasion, and migration of highly metastatic human gastric adenocarcinoma AGS cells by inhibiting the activation of FAK and PI3K/Akt signals, which in turn downregulates MMP-2 and -9 expression and activity [197]. Finally, nobiletin inhibited the epithelial–mesenchymal transition of human non-small cell lung cancer cells by antagonizing the TGF-β1/Smad3 signaling pathway, thus prohibiting the growth of metastatic nodules in the lungs of nude mice [198]. …”