ABSTRACT
Expression of the CD44 gene is upregulated in breast cancer cells and is correlated with patient survival. Aberrant CD44 expression promotes tumor progression and metastasis. In the present study, we investigated the role of zerumbone (ZER) on regulatory mechanisms of CD44 expression in breast cancer cells. Our results showed that CD44 expression was significantly increased by epidermal growth factor receptor (EGFR) ligands in SKBR3 breast cancer cells. In contrast, EGF-induced CD44 expression was decreased by a MEK1/2 inhibitor, UO126, or STAT3 inhibitor, STAT3 VI, respectively. Notably, ZER downregulated the basal level of CD44 expression in CD44+ breast cancer cells. In addition, the induction of CD44 expression by EGFR ligands, EGF or TGF-α, was markedly decreased by ZER treatment. Finally, we investigated the inhibitory mechanism of ZER on EGF-induced CD44 expression. Our results showed that EGF-induced phosphorylation of STAT3 was completely suppressed by ZER. Collectively, ZER suppressed EGF-induced CD44 expression through inhibition of the STAT3 pathway. Therefore, we suggested that ZER may act as a promising therapeutic drug for the treatment of breast cancer.
Subject(s)
Breast Neoplasms/drug therapy , Epidermal Growth Factor/genetics , Hyaluronan Receptors/biosynthesis , STAT3 Transcription Factor/biosynthesis , Sesquiterpenes/administration & dosage , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , ErbB Receptors , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , STAT3 Transcription Factor/antagonists & inhibitors , Signal Transduction/drug effects , Transcriptional Activation/drug effects , Transforming Growth Factor alpha/geneticsABSTRACT
Fibronectin (FN) plays a major role in cell adhesion, migration and oncogenic transformation. Aberrant FN expression is associated with poor prognosis in various types of cancer, including breast cancer. In this study, we investigated the effect of silibinin on the epidermal growth factor (EGF)-induced FN expression in triple negative breast cancer (TNBC) cells. Our data showed that the levels of FN mRNA and protein expression were dose-dependently increased by EGF in MDA-MB468 and BT20 breast cancer cells. Consequently, EGF-induced FN expression was decreased by the epidermal growth factor receptor (EGFR) inhibitors AG1478 and gefitinib. EGF-induced FN expression was also decreased by MEK1/2, PI3K and STAT3 specific inhibitors. In the present study, we observed for the first time that EGF-induced FN expression was significantly decreased by silibinin treatment in TNBC cells. Furthermore, we found that silibinin suppressed the EGF-induced phosphorylation of STAT3 but not Erk and Akt. Taken together, silibinin downregulated EGF-induced FN expression through the inhibition of STAT3 phosphorylation in TNBC cells. Silibinin may be a promising anticancer drug for the treatment of TNBC.
Subject(s)
Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Fibronectins/genetics , Fibronectins/metabolism , Silymarin/pharmacology , Triple Negative Breast Neoplasms/metabolism , Cell Line, Tumor , Female , Gefitinib , Humans , MCF-7 Cells , Phosphorylation , Quinazolines/pharmacology , Signal Transduction , Silybin , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Tyrphostins/pharmacologyABSTRACT
BACKGROUND/AIMS: Berberine (BBR) is an isoquinoline alkaloid and is beneficial for the anticancer effect on a variety of human tumor cells. However, BBR's anti-angiogenesis property and its clinical potential as an inhibitor of tumor angiogenesis in breast cancer cells have not been fully elucidated. Here, we investigated the effect of BBR on TPA-induced VEGF and fibronectin (FN) as well as VEGF-induced FN in breast cancer cells. METHODS: The secretion of VEGF protein was detected by ELISA. Fibronectin mRNA and protein expression was analyzed by Real-Time PCR and western blotting, respectively. The overexpressions of CA-MEK, and CA-Akt were examined by adenovirus system. RESULTS: Our results showed that TPA, a tumor promoter, significantly increased the level of VEGF and FN expression in both MCF7 and T47D breast cancer cells. On the other hand, TPA-induced VEGF and FN expression was suppressed by LY294002, a PI-3K inhibitor. In contrast, the level of FN expression also significantly increased by constitutively active (CA)-AKT overexpression. We also found that TPA-induced VEGF and FN expression was decreased by BBR treatment. Finally, our results showed that VEGF augmented the expression of FN whereas VEGF-induced FN expression was decreased by BBR treatment. CONCLUSION: Taken together, we suggest that BBR may suppress TPA-induced VEGF and FN as well as VEGF-induced FN through the inhibition of the PI-3K/AKT pathway in breast cancer cells. Therefore, we suggest that BBR may be used as a candidate drug for the inhibition of angiogenesis of human breast cancer.
