ginsenoside-rg3 and Breast-Neoplasms

Ginsenoside Rg3 exerts antiproliferation activity on cancer cells by regulating diverse noncoding RNAs. However, little is known about the role of long noncoding RNAs (lncRNAs) or their relationship with competitive endogenous RNA (ceRNA) in Rg3-treated cancer cells. Here, a lncRNA (ATXN8OS) was found to be downregulated via Rg3-mediated promoter hypermethylation in MCF-7 breast cancer cells. SiRNA-induced downregulation of ATXN8OS decreased cell proliferation but increased apoptosis, suggesting that the noncoding RNA possessed proproliferation activity. An in silico search for potential ATXN8OS-targeting microRNAs (miRs) identified a promising candidate (miR-424-5p) based on its high binding score. As expected, miR-424-5p suppressed proliferation and stimulated apoptosis of the MCF-7 cells. The in silico miR-target-gene prediction identified 200 potential target genes of miR-424-5p, which were subsequently narrowed down to seven that underwent hypermethylation at their promoter by Rg3. Among them, three genes (EYA1, DACH1, and CHRM3) were previously known oncogenes and were proven to be oppositely regulated by ATXN8OS and miR-424-5p. When taken together, Rg3 downregulated ATXN8OS that inhibited the tumor-suppressive miR-424-5p, leading to the downregulation of the oncogenic target genes.

Topics: Base Sequence; Breast Neoplasms; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Ginsenosides; Humans; MicroRNAs; Models, Biological; RNA, Long Noncoding

Ginsenoside Rg3 (Rg3) has been studied in several cancer models and is suggested to act through various pharmacological effects. We investigated the anticancer properties of Rg3 through myeloid-derived suppressor cell (MDSC) modulation in FM3A mouse mammary carcinoma cells. The effects of Rg3 on MDSCs and consequent changes in cancer stem-like cells (CSCs) and epithelial-mesenchymal transition (EMT) were evaluated by diverse methods. MDSCs promoted cancer by enhancing breast cancer stemness and promoting EMT. Rg3 at a dose without obvious cytotoxicity downregulated MDSCs and repressed MDSC-induced cancer stemness and EMT. Mechanistic investigations suggested that these inhibitory effects of Rg3 on MDSCs and corresponding cancer progression depend upon suppression of the STAT3-dependent pathway, tumor-derived cytokines, and the NOTCH signaling pathway. In a mouse model, MDSCs accelerated tumor progression, and Rg3 delayed tumor growth, which is consistent with the results of in vitro experiments. These results indicated that Rg3 could effectively inhibit the progression of breast cancer. The anticancer effect of Rg3 might be partially due to its downregulation of MDSCs and consequent repression of cancer stemness and EMT in breast cancer. Hence, we suggest the regulation of MDSCs through Rg3 treatment as an effective therapeutic strategy for breast cancer patients.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Female; Ginsenosides; Mice; Mice, Inbred C3H; Myeloid-Derived Suppressor Cells; Neoplastic Stem Cells

Ginsenoside Rg3 is a key metabolite of ginseng and is known to inhibit cancer cell growth. However, the epigenetics of CpG methylation and its regulatory mechanism have yet to be determined. Genome-wide methylation analysis of MCF-7 breast cancer cells treated with Rg3 was performed to identify epigenetically regulated genes and pathways. The effect of Rg3 on apoptosis and cell proliferation was examined by a colony formation assay and a dye-based cell proliferation assay. The association between methylation and gene expression was monitored by RT-PCR and Western blot analysis. Genome-wide methylation analysis identified the "cell morphology"-related pathway as the top network. Rg3 induced late stage apoptosis but inhibited cell proliferation up to 60%. Hypermethylated TRMT1L, PSMC6 and NOX4 were downregulated by Rg3, while hypomethylated ST3GAL4, RNLS and KDM5A were upregulated. In accordance, downregulation of NOX4 by siRNA abrogated the cell growth effect of Rg3, while the effect was opposite for KDM5A. Notably, breast cancer patients with a higher expression of NOX4 and KDM5A showed poor and good prognosis of survival, respectively. In conclusion, Rg3 deregulated tumor-related genes through alteration of the epigenetic methylation level leading to growth inhibition of cancer cells.

Topics: Breast Neoplasms; Cell Proliferation; Epigenesis, Genetic; Genome-Wide Association Study; Ginsenosides; Humans; MCF-7 Cells; Methylation; NADPH Oxidase 4; Prognosis; Retinoblastoma-Binding Protein 2

Ginsenoside Rg3 is an extract from the natural product ginseng. Previous studies have linked Rg3 with anti-metastasis of cancer in vivo and in vitro. CXC receptor 4 (CXCR4) is a vital molecule in migration and homing of cancer to the docking regions.. In this study, the effects of Rg3 on CXCR4 expression were investigated in a breast cancer cell line. Immunohistochemistry, chemotaxis and wound healing mobility assays were performed in cultured MDA-MB-231 cells.. At a dosage without obvious cytotoxicity, Rg3 treatment elicits a weak CXCR4 stain color, decreases the number of migrated cells in CXCL12-elicited chemotaxis and reduces the width of the scar in wound healing.. This work suggests that Rg3 is a new CXCR4 inhibitor from a natural product.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokine CXCL12; Chemotaxis; Drugs, Chinese Herbal; Female; Ginsenosides; Humans; Receptors, CXCR4; Wound Healing

To explore the inhibiting effect of ginsenoside Rg3 on the growth and angiogenesis of orthotopically xenotransplanted human breast infiltrating duct carcinoma in nude mice.. A total of 15 female nude mice having received xenotransplanted human breast infiltrating duct carcinoma were randomly divided into 3 groups. Ginsenoside Rg3 (5 mg/kg, qd), cyclophosphamid (26 mg/kg, qod) and control solution (0.5% sodium carboxymethyl cellulose, qd) were given to each group by gas-trogavage in 0.5 ml volume for 56 days. Breast cancer masses were collected for light microscope observation. The intra-tumoral microvessel density (MVD) and the expression of vascular endothelial growth factor(VEGF) were examined by immunohis-tochemical staining.. The tumor weight of CTX group was significantly lower than that of control group (P < 0.05), and the comparison between those of Rg3 group and control group was nearly reaching significant level. The MVD and VEGF of Rg3 group by immunohistochemical staining were significantly lower than those of control group (P < 0.05).. Rg3 could inhibit the growth and angiogenesis of xenotransplanted human breast infiltrating duct carcinoma in nude mice.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Carcinoma, Ductal, Breast; Female; Ginsenosides; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Random Allocation; Vascular Endothelial Growth Factor A