Berberine down-regulates IL-8 expression through inhibition of the EGFR/MEK/ERK pathway in triple-negative breast cancer cells.

Interleukin-8 (IL-8) expression is associated with metastasis in a variety of cancer cells. Here, we investigated the regulatory mechanism of IL-8 expression as well as the pharmacological effect of berberine (BBR) on IL-8 expression in triple-negative breast cancer (TNBC) cells. The clinical value of IL-8 was analyzed by from a public database [Kaplan‑Meier plotter database. IL-8 mRNA and protein expression was analyzed by real-time PCR and ELISA, respectively. Cell invasion was analyzed by Boyden chamber assay. Tumor cell growth was analyzed by colony forming assay. Clinically, we observed that breast cancer patients with highly expressed IL-8 are associated with poor outcomes in areas such as relapse-free, overall, and distant metastasis-free survival. We showed that IL-8 expression is higher in TNBC cells than in non-TNBC cells. In addition, the rates of cell invasion were significantly increased by IL-8 treatment. These IL-8 levels were decreased by EGFR (Neratinib and Afatinib) and MEK (PD98059) inhibitors in TNBC cells. Finally, we observed that BBR dramatically suppresses IL-8 expression. In addition, BBR also inhibited cell invasiveness and anchorage-independent growth. Interestingly, our results showed that BBR down-regulates EGFR protein expression and dose-dependently inhibits MEK and ERK phosphorylation. Here, we demonstrate that BBR may be a promising drug to suppress cell invasiveness and growth of TNBC through IL-8-related mechanisms.

Kim S ，You D ，Jeong Y ，Yu J ，Kim SW ，Nam SJ ，Lee JE ... -  《-》

Berberine Suppresses Cell Motility Through Downregulation of TGF-β1 in Triple Negative Breast Cancer Cells.

Kim S ，Lee J ，You D ，Jeong Y ，Jeon M ，Yu J ，Kim SW ，Nam SJ ，Lee JE ... -  《-》

MEK-dependent IL-8 induction regulates the invasiveness of triple-negative breast cancer cells.

Kim S ，Lee J ，Jeon M ，Lee JE ，Nam SJ ... -  《-》

Pharmacotranscriptomic profiling of resistant triple-negative breast cancer cells treated with lapatinib and berberine shows upregulation of PI3K/Akt signaling under cytotoxic stress.

Triple-negative breast cancer (TNBC) is the most incurable type of breast cancer, accounting for 15-20% of breast cancer cases. Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and Her2, and berberine (BBR) is a plant-based alkaloid suggested to inhibit several cancer signaling pathways. We previously reported that lapatinib activates the Akt oncoprotein in MDA-MB231 TNBC cells. The present study determined the mechanism(s) of Akt activation in response to lapatinib, BBR, and capivasertib (Akt inhibitor) as well as the role of Akt signaling in chemoresistance in TNBC cells. Genetic profiles of 10 TNBC cell lines and patients were analyzed using datasets obtained from Gene Expression Omnibus and The Cancer Genome Atlas Database. Then, the effects of lapatinib, BBR, and capivasertib on treated MDA-MB231 and MCF-7 cell lines were studied using cytotoxicity, immunoblot, and RNA-sequencing analyses. For further confirmation, we also performed real-time PCR for genes associated with PI3K signaling. MDA-MB231 and MCF-7 cell lines were both strongly resistant to capivasertib largely due to significant Akt activation in both breast cancer cell lines, while lapatinib and BBR only enhanced Akt signaling in MDA-MB231 cells. Next-generation sequencing, functional enrichment analysis, and immunoblot revealed downregulation of CDK6 and DNMT1 in response to lapatinib and BBR lead to a decrease in cell proliferation. Expression of placental, fibroblast growth factor, and angiogenic biomarker genes, which are significantly associated with Akt activation and/or dormancy in breast cancer cells, was significantly upregulated in TNBC cells treated with lapatinib and BBR. Lapatinib and BBR activate Akt through upregulation of alternative signaling, which lead to chemoresistance in TNBC cell. In addition, lapatinib overexpresses genes related to PI3K signaling in resistant TNBC cell model.

Jabbarzadeh Kaboli P ，Luo S ，Chen Y ，Jomhori M ，Imani S ，Xiang S ，Wu Z ，Li M ，Shen J ，Zhao Y ，Wu X ，Hin Cho C ，Xiao Z ... -  《-》

Different mechanisms involved in the berberine-induced antiproliferation effects in triple-negative breast cancer cell lines.

Berberine (BBR) is known to be effective at inhibiting cell proliferation and promoting apoptosis in various cancer cells. However, the effects of BBR on triple-negative breast cancer (TNBC) cells remain unclear. The aim of this study was to investigate the cell inhibition effects of BBR on different subtypes of TNBC cells. Using human TNBC cell lines of different subtypes, namely, MDA-MB-231, MDA-MB-468, MDA-MB-453, and BT-549 as in vitro models, antiproliferative effects of BBR were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, trypan blue exclusion assay, and clonogenic assay. Furthermore, cell apoptosis and autophagy were analyzed by flow cytometry, immunofluorescent staining, and LC3 I/II-targeted Western blotting. Various cell growth-related signaling pathways (AKT/ERK/p38) and the expression of proteins present in various cell cycle kinase complexes were analyzed by Western blotting. BBR concentration-dependently suppressed cell proliferation in MDA-MB-468 (0, 3, 6, and 12 μM) and MDA-MB-231 (0, 6.25, 12.5, and 25 μM). The inhibitory effect was not brought about by inducing cell apoptosis, necrosis, or autophagy. Cell cycle analysis disclosed an increased S+G2/M fraction among the BBR-treated MDA-MB-231 and MDA-MB-453 cells; while with the BBR-treated MDA-MB-468 and BT-549 lines, an increased G0/G1 fraction was found. In MDA-MB-231 and MDA-MB-453 cells, by Western blotting, BBR decreased the expression of Cyclin A and CDK1, On the other hand, in BBR-treated MDA-MB-468 and BT-549 cells, there was a decrease in Cyclin D and CDK4 expression. Our results demonstrate that the antiproliferation effects of BBR occur via different mechanisms in different subtypes of TNBC cells, which suggests that BBR has potential as a personalized treatment for TNBC patients.

Lin YS ，Chiu YC ，Tsai YH ，Tsai YF ，Wang JY ，Tseng LM ，Chiu JH ... -  《-》