Antitumor and Anti-Invasive Effect of Apigenin on Human Breast Carcinoma through Suppression of IL-6 Expression

• Published in: International journal of molecular sciences 2019-06, Vol.20 (13), p.3143
• Main Authors: Lee, Hwan Hee, Jung, Joohee, Moon, Aree, Kang, Hyojeung, Cho, Hyosun
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Animals; anti-invasive; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; antitumor; Antitumor activity; apigenin; Apigenin - pharmacology; Apigenin - therapeutic use; Apoptosis; Aromatase; Breast cancer; Breast carcinoma; Cadherin; Carcinoma - drug therapy; Cell adhesion & migration; Cell cycle; Cell growth; Cell proliferation; Cyclin B1; Cyclin D1; Cyclin-dependent kinase 2; Cyclin-dependent kinase 4; Cyclin-dependent kinase inhibitor p21; Cyclins; Cyclins - genetics; Cyclins - metabolism; Cytokines; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Flavonoids; Growth factors; human breast carcinoma; Humans; Inflammation; Interleukin 6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Invasiveness; Janus kinase; Kinases; Mammary Neoplasms, Experimental - drug therapy; MAP kinase; MCF-7 Cells; Medical prognosis; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular modelling; Morphology; N-Cadherin; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Prostate; Protein kinase; Proteins; Signal Transduction - drug effects; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Tumor necrosis factor-TNF; Tumors; Vascular endothelial growth factor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20133143

Interleukin (IL)-6 plays a crucial role in the progression, invasion, and metastasis of breast cancer. Triple-negative breast cancer (TNBC) cell line MDA-MB-231 is known for its aggressive metastasis. Epithelial to mesenchymal transition (EMT) is a critical process in cancer metastasis. The positive correlation between IL-6 and EMT in tumor microenvironment is reported. We found significantly upregulated IL-6 expression in MDA-MB-231 cells. A blockade of IL-6 expression decreased levels of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), phosphorylated protein kinase B (pAkt), and cell cycle-related molecules, including cyclin-dependent kinases (CDKs) and cyclins in MDA-MB-231 cells. A short-hairpin RNA (shRNA)-mediated blockade of IL-6 expression inhibited migration and N-cadherin expression and induced E-cadherin expression in MDA-MB-231 cells. Growth rate was slower for the tumors derived from IL-6 shRNA-treated MDA-MB-231 cells than for those derived from control shRNA-treated MDA-MB-231 cells. The expression of pSTAT3, phosphorylated extracellular signal-regulated kinase (pERK), PI3K, pAkt, snail, vimentin, and N-cadherin was significantly lower in tumors from IL-6 shRNA-treated MDA-MB cells. In addition, apigenin treatment significantly inhibited the growth of MDA-MB-231-derived xenograft tumors along with the protein expressions of pSTAT3, pERK, IL-6, PI3K, pAkt, and N-cadherin. Our results demonstrate that the anti-invasive effect of apigenin in MDA-MB-231-derived xenograft tumors is mediated by the inhibition of IL-6-linked downstream signaling pathway.