Emodin represses TWIST1-induced epithelial-mesenchymal transition in head and neck squamous cell carcinoma cells through the inhibition of β-catenin and Akt pathways

[[abstract]]Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer deaths worldwide. In recent studies, a crucial link has been discovered between the acquisition of metastatic traits and tumour-initiating abilities in cancer cells during the epithelial–mesenchymal transition (EMT). Herein, we demonstrated that the ectopic expression of TWIST1, the EMT regulator, in HNSCC FaDu cells triggered EMT and resulted in the acquisition of a mesenchymal phenotype. Moreover, FaDu-pFLAG-TWIST1 cancer cell populations that were induced to EMT displayed an increased proportion of cells with the CD44 marker, which is associated with tumour initiation. Interestingly, we found that emodin treatment reduced the tumour-initiating abilities and inhibited cell migration and invasion in FaDu-pFLAG-TWIST1 cells. Emodin directly inhibited TWIST1 expression, upregulated E-cadherin mRNA and protein expression, and downregulated vimentin mRNA and protein expression. Moreover, we found that emodin inhibited TWIST1 binding to the E-cadherin promoter and repressed E-cadherin transcription activity. We also found that emodin inhibited TWIST1-induced EMT by inhibiting the β-catenin and Akt pathways. More interestingly, emodin significantly inhibited TWIST1-induced invasion in vivo. Therefore, emodin might be applicable to anticancer therapy and could be a potential new therapeutic drug for HNSCC

Black Tea Polyphenol Theaflavins Inhibit Aromatase Activity and Attenuate Tamoxifen Resistance in Her2/Neu-Transfected Human Breast Cancer Cells through Tyrosine Kinase Suppression

The aromatase enzyme, which converts androstenedione to oestrone, regulates the availability of oestrogen to support the growth of hormone- dependent breast tumours. In this study, we investigated the inhibitory effects of black tea polyphenols on aromatase activities. We found that black tea polyphenols, TF-1, TF-2 and TF-3, significantly inhibited rat ovarian and human placental aromatase activities. In addition, using an in vivo model, these black tea polyphenols also inhibited the proliferation induced by 100 nM dehydroepiandrosterone (DHEA) in MCF-7 cells. Transfection of HER2/neu in MCF-7 breast cancer cells appeared to be associated with an increased resistance of the cells to hormonal therapy. Interestingly, unlike the selective oestrogen receptor modulator (SERM) tamoxifen, black tea polyphenols had antiproliferation effects in breast cancer cells with hormonal resistance. The inhibitory effect of black tea polyphenols on hormone-resistant breast cancer cells suppressed the basal receptor tyrosine phosphorylation in HER2/neu-overexpressing MCF-7 cells. These findings suggest the use of black tea polyphenols may be beneficial in the chemoprevention of hormone-dependent breast tumours and represent a possible remedy to overcome hormonal resistance of hormone-independent breast tumours. ( C) 2004 Elsevier Ltd. All rights reserve

Pu-Erh Tea Attenuates Hyperlipogenesis and Induces Hepatoma Cells Growth Arrest through Activating Amp-Activated Protein Kinase (Ampk) in Human Hepg2 Cells

In the present study, we successively extracted the pu-erh raw tea with methanol (PR-1), chloroform (PR-2), ethyl acetate (PR-3), n-butanol (PR-4) , and water (PR-5). Among these extracts, PR-3 extract contained ingredients with the most effective hypolipidemic potential and was further purified by column chromatography. Moreover, chronic administration of PR-3 provoked a significant reduction in levels of serum triglyceride and low-density lipoprotein ( LDL) in rats. Our study demonstrated that fraction 5 from the PR-3 extract (PR-3-5s) showed a hypolipidemic effect in human hepatoma HepG2 cells. PR-3-5s decreased the expression of fatty acid synthase (FASN) and inhibited the activity of acetyl-coenzyme A carboxylase (ACC) by stimulating AMP- activated protein kinase (AMPK) through the LKB1 pathway. Moreover, PR-3-5s blocked the progression of the cell cycle at the G1 phase by inducing p53 expression and in turn upregulating p21 expression

Apigenin Induces Apoptosis through Proteasomal Degradation of Her2/Neu in Her2/Neu-Overexpressing Breast Cancer Cells Via the Phosphatidylinositol 3-Kinase/Akt-Dependent Pathway

Apigenin is a low toxicity and non-mutagenic phytopolyphenol and protein kinase inhibitor. It exhibits anti- proliferating effects on human breast cancer cells. Here we examined several human breast cancer cell lines having different levels of HER2/neu expression and found that apigenin exhibited potent growth-inhibitory activity in HER2 /neu-overexpressing breast cancer cells but was much less effective for those cells expressing basal levels of HER2/ neu. Induction of apoptosis was also observed in HER2/neu- overexpressing breast cancer cells in a dose- and time- dependent manner. However, the one or more molecular mechanisms of apigenin-induced apoptosis in HER2/neu- overexpressing breast cancer cells remained to be elucidated . A cell survival pathway involving phosphatidylinositol 3- kinase (PI3K), and Akt is known to play an important role in inhibiting apoptosis in response to HER2/neu- overexpressing breast cancer cells, which prompted us to investigate whether this pathway plays a role in apigenin-induced apoptosis in HER2/ neu-overexpressing breast cancer cells. Our results showed that apigenin inhibits Akt function in tumor cells in a complex manner. First, apigenin directly inhibited the PI3K activity while indirectly inhibiting the Akt kinase activity. Second, inhibition of HER2/neu autophosphorylation and transphosphorylation resulting from depleting HER2/neu protein in vivo was also observed. In addition, apigenin inhibited Akt kinase activity by preventing the docking of PI3K to HER2/HER3 heterodimers. Therefore, we proposed that apigenin-induced cellular effects result from loss of HER2/ neu and HERS expression with subsequent inactivation of PI3K and AKT in cells that are dependent on this pathway for cell proliferation and inhibition of apoptosis. This implies that the inhibition of the HER2/ HERS heterodimer function provided an especially effective strategy for blocking the HER2/neu-mediated transformation of breast cancer cells. Our results also demonstrated that apigenin dissociated the complex of HER2/ neu and GRP94 that preceded the depletion of HER2/neu. Apigenin-induced degradation of mature HER2/neu involves polyubiquitination of HER2/neu and subsequent hydrolysis by the proteasome

Degradation of Her2/Neu by Apigenin Induces Apoptosis through Cytochrome C Release and Caspase-3 Activation in Her2/Neu-Overexpressing Breast Cancer Cells

We have shown that exposure of the HER2/neu-overexpressing breast cancer cells to apigenin resulted in induction of apoptosis by depleting HER2/neu protein and, in turn, suppressing the signaling of the HER2/HER3-PI3K/Akt pathway. Here, we examined whether inhibition of this pathway played a role in the anti-tumor effect. The results revealed that treatment with apigenin induced apoptosis through cytochrome c release and caused a rapid induction of caspase-3 activity and stimulated proteolytic cleavage of DFF-45. Furthermore, apigenin downregulated cyclin D1, D3 and Cdk4 and increased p27 protein levels. Colony formation in the soft agar assay, a hallmark of the transformation phenotype, was preferentially suppressed in HER2/neu-overexpressing breast cancer cells in the presence of apigenin. In addition , a structure–activity relationship study indicated that (1 ) the position of B ring; and (2) the existence of the 3′,4′-hydroxyl group on the 2-phenyl group were important for the depletion of HER2/neu protein by flavonoids. These results provided new insights into the structure–activity relationship of flavonoids

Beneficial Effects of Different Tea Flowers against Human Breast Cancer Mcf-7 Cells

Tea is a popular beverage with health benefits. The enriched tea polyphenols including catechins have been reported to perform anti-cancer, anti-oxidant, anti-inflammatory and anti-bacterial activity. In this study, we compared the levels of catechins and caffeine in tea flowers from six different species of Camellia japonica, Camellia tenuifolia. Camellia oleifera, 2 savoury Camellias and Camellia sinensis. C sinensis detected a variety of catechins, while only (+)-catechin and (-)- epicatechin can be detected by the iso-cratic HPLC system in other tea flowers. The total catechin content was also lower in these tea flowers. In addition, the water extract of tea flowers was used to test the biological functions including anti-proliferative and apoptotic effects in human breast cancer MCF-7 cells. The water extract of C sinensis remained most active among six different species using both MTT assays and the cleavage analysis of apoptosis-related molecules, PARP and Bid. The major bioactivity of C. sinensis comes from (-)-epigallo- catechin-3-gallate and (-)-epigallocatechin, not detected in other five species. Interestingly, we found that C. tenuifolia still had potent bioactivity. It is likely that bioactive molecules other than catechins exist in C tenuifolia

Isolation of eugenyl β-primeveroside from Camellia sasanqua and its anticancer activity in PC3 prostate cancer cells

Most studies of tea trees have focused on their ornamental properties, there are fewer published studies on their medical values. The purpose of this study was to compare the chemical constituents and the biological potential of the water extract of leaves in eight species of Camellia including Camellia sinensis. Among eight Camellia species, Camellia sasanqua showed potent anticancer activities in prostate cancer PC3 cells. In addition to catechins, the major component, eugenyl β-primeveroside was detected in C. sasanqua. Eugenyl β-primeveroside blocked the progression of cell cycle at G1 phase by inducing p53 expression and further upregulating p21 expression. Moreover, eugenyl β-primeveroside induced apoptosis in PC3 prostate cancer cells. Our results suggest that C. sasanqua may have anticancer potential