Apigenin induces caspase-dependent apoptosis by inhibiting signal transducer and activator of transcription 3 signaling in HER2-overexpressing SKBR3 breast cancer cells

Abstract

Phytoestrogens have been demonstrated to inhibit tumor induction; however, their molecular mechanisms of action have remained elusive. The present study aimed to investigate the effects of a phytoestrogen, apigenin, on proliferation and apoptosis of the human epidermal growth factor receptor 2 (HER2)-expressing breast cancer cell line SKBR3. Proliferation assay, MTT assay, fluorescence-activated cell sorting analysis, western blot analysis, immunocytochemistry, reverse transcription-polymerase chain reaction and ELISA assay were used in the present study. The results of the present study indicated that apigenin inhibited the proliferation of SKBR3 cells in a dose-and time-dependent manner. This inhibition of growth was accompanied by an increase in the sub-G0/G1 apoptotic population. Furthermore, apigenin enhanced the expression levels of cleaved caspase-8 and -3, and induced the cleavage of poly(adenosine diphosphate ribose) polymerase in SKBR3 cells, confirming that apigenin promotes apoptosis via a caspase-dependent pathway. Apigenin additionally reduced the expression of phosphorylated (p)-janus kinase 2 and p-signal transducer and activator of transcription 3 (STAT3), inhibited CoCl2-induced vascular endothelial growth factor (VEGF) secretion and decreased the nuclear localization of STAT3. The STAT3 inhibitor S31-201 decreased the cellular proliferation rate and reduced the expression of p-STAT3 and VEGF. Therefore, these results suggested that apigenin induced apoptosis via the inhibition of STAT3 signaling in SKBR3 cells. In conclusion, the results of the present study indicated that apigenin may be a potentially useful compound for the prevention or treatment of HER2-overexpressing breast cancer.

An Insight into the Putative Role of Victuals Like Honey and its Polyphenols in Breast Cancer

“…The PI3K activity was directly affected by apigenin while AKT kinase activity was ambiguously affected. All these results were apigenin-dose dependent 65,66 . p53-dependent apoptosis was induced by apigenin in T47D and MDA-MB-231 breast cancer cell lines.…”

“…Polyphenols like caffeic acid [64][65][66][67][68][69][70] , chrysin [87][88][89][90][91] , quercetin, kaempferol [98][99][100][101][102] and ellagic acid 106 are found to down-regulate the matrix metallopeptidase in diverse breast cancer cells like MCF-7 and MDA-MB-231. Matrix metallopeptidases (MMP) is an enzyme that belong to zinc-metalloproteinases family and tangled in the degradation of extracellular matrix during physiological procedures, such as, development of the embryo, wound healing, cell migration, angiogenesis, etc.…”

Apigenin enhances the cisplatin cytotoxic effect through p53-modulated apoptosis

“…This compound has been reported to induce cell cycle arrest, in addition to apoptosis when used at varying concentrations (39). In the current study, apigenin had the ability to amplify cisplatin-induced apoptosis of cancer cells.…”

Plant Flavone Apigenin: an Emerging Anticancer Agent

“…Therefore, the estrogenicity of the phytochemicals contributes to the stimulation of cellular proliferation or reduction in aromatase activity, suggesting that these flavonoids must be used with caution [55]. In HER2-overexpressing breast cancer cells, apigenin-exerted anti-proliferative activity by inhibiting STAT3 signaling, suggesting its potential as a preventive agent [56]. In addition, apigenin also down-regulated STAT3 target genes MMP-2, MMP-9, VEGF and Twist1, which are involved in cell migration and invasion of breast cancer cells [56–58].…”