Phloroglucinol suppresses metastatic ability of breast cancer cells by inhibition of epithelial-mesenchymal cell transition.
Bottom Line: Importantly, phloroglucinol decreased SLUG through inhibition of PI3K/AKT and RAS/RAF-1/ERK signaling.In agreement with in vitro data, phloroglucinol was also effective against in vivo metastasis of breast cancer cells, drastically suppressing their metastatic ability to lungs, and extending the survival time of mice.Collectively, our findings demonstrate a novel anticancer activity of phloroglucinol against metastasis of breast cancer cells, implicating its clinical relevance.
Affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, South Korea.Show MeSH
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Mentions: Tumor cell invasion is involved with the loss of cell–cell interaction together with acquisition of migratory properties, and is often associated with EMT.5 We next examined whether phloroglucinol suppresses the migratory and invasive properties of breast cancer cells through inhibition of EMT. To this end, we examined whether phloroglucinol decreases mesenchymal cell markers. Importantly, treatment with phloroglucinol decreased mesenchymal cell markers such as N-cadherin, FN1 and VIM, while increasing epithelial cell marker E-cadherin in basal type breast cancer cells (Fig.2a,b). Since these EMT markers are directly regulated by the EMT transcription factors such as SLUG, SNAIL, ZEB1 and TWIST, we analyzed whether phloroglucinol could inhibit the expression of these EMT regulators. Notably, SLUG expression was markedly decreased by treatment with phloroglucinol, whereas SNAIL, ZEB1 and TWIST expression were not altered (Fig.2c). Because phloroglucinol decreased only SLUG among four EMT transcription factors, we next examined whether downregulation of SLUG alone can suppress EMT. As expected, treatment with siRNA targeting SLUG caused a decrease of mesenchymal cell markers such as FN1, VIM and N-cadherin, while it increased E-cadherin in breast cancer cells (Fig.2d). In agreement, downregulation of SLUG effectively suppressed migratory and invasive properties of breast cancer cells (Fig.2e). Taken together, these results suggest that phloroglucinol suppresses mesenchymal phenotypes of breast cancer cells through downregulation of SLUG.
Affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, South Korea.