Apigenin inhibits TNFα/IL-1α-induced CCL2 release through IKBK-epsilon signaling in MDA-MB-231 human breast cancer cells

Abstract

Mortality associated with breast cancer is attributable to aggressive metastasis, to which TNFα plays a central orchestrating role. TNFα acts on breast tumor TNF receptors evoking the release of chemotactic proteins (e.g. MCP-1/CCL2). These proteins direct inward infiltration/migration of tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), T-regulatory cells (Tregs), T helper IL-17-producing cells (Th17s), metastasis-associated macrophages (MAMs) and cancer-associated fibroblasts (CAFs). Tumor embedded infiltrates collectively enable immune evasion, tumor growth, angiogenesis, and metastasis. In the current study, we investigate the potential of apigenin, a known anti-inflammatory constituent of parsley, to downregulate TNFα mediated release of chemokines from human triple-negative cells (MDA-MB-231 cells). The results show that TNFα stimulation leads to large rise of CCL2, granulocyte macrophage colony-stimulating factor (GMCSF), IL-1α and IL-6, all suppressed by apigenin. While many aspects of the transcriptome for NFkB signaling were evaluated, the data show signaling patterns associated with CCL2 were blocked by apigenin and mediated through suppressed mRNA and protein synthesis of IKBKe. Moreover, the data show that the attenuation of CCL2 by apigenin in the presence TNFα paralleled the suppression of phosphorylated extracellular signal-regulated kinase 1 (ERK 1/ 2). In summary, the obtained findings suggest that there exists a TNFα evoked release of CCL2 and other LSP recruiting cytokines from human breast cancer cells, which can be attenuated by apigenin.

Whole Transcriptomic Analysis of Apigenin on TNFα Immuno-activated MDA-MB-231 Breast Cancer Cells

“…A non-lethal working concentration in MDA-MB-231 cells was established for TNFα, apigenin (as previously reported) (22) and IL1α (Figure 1) where the sub-lethal working concentrations were set at the following: 40 μM apigenin and 40 ng/ml TNFα. To investigate TNFα-mediated induction of chemokines and the influence of apigenin, whole transcriptomic microarray analysis was conducted using the Affymetrix gene atlas system.…”

“…Apigenin is a natural compound which has the capacity to antagonize several mitigating events in human tumor development and tumor immune evasion. These include the capability to reduce inflammation, inhibit casein kinase 2 (CK2), matrix metalloproteinases 9 and 1, protein kinase C (18), cytochrome P450 1A1 (19) topoisomerase I (20) tumor growth factors (21), CCL2-induced release by TNFαactivated breast cancer (22) and blockade of drug resistanceassociated extrusion pumps (23,24). In the current study, we expand on our previous work by evaluating the effects of apigenin on TNFα-treated MDA-MB-231 cells (22) by analyzing the whole transcriptome.…”

The inhibitory effects of butein on cell proliferation and TNF-α-induced CCL2 release in racially different triple negative breast cancer cells

“…This gene also regulates survival signaling associated with NFκB pathway activation, enabling cell transformation [76,78]. Also, Bauer et al [79] studied the association between the IKBKE gene and CCL2 release, showing that IKBKE downregulation attenuates CCL2 expression in MDA-MB-231 TNBC cells. Likewise, the data from our previous study [80] demonstrated that the natural compound Plumbagin inhibited IKBKE gene expression and consequent release of CCL2 in TNF-α-induced MDA-MB-231 cells, strengthening the potential association between IKBKE and CCL2 expression.…”

Mechanistic evaluation of phytochemicals in breast cancer remedy: current understanding and future perspectives

“…The inhibition of CCL2 by apigenin occurred through suppression of IKBKe signalling. [163][164][165][166][167][168][169][170][171][172] Apigenin overcame drug resistance and decreased colonization and cell growth in adriamycinresistant MCF-7 cells via downregulation of MDR1 and Pglycoprotein, as well as, suppression of STAT3 signalling and its nuclear translocation. The compound also diminished the secretion of MMP-9 and VEGF (STAT3 target genes) in these cells.…”