Sustained ERK activation is involved in the kaempferol-induced apoptosis of breast cancer cells and is more evident under 3-D culture condition

Abstract

In order to determine the effects of a variety of flavonoids, we applied differing amounts of several flavonoids to human breast cancer cells. Kaempferol treatment resulted in significant reduction of cell viability in the MCF-7 cells, although it exerted only minor effect on the cell viability of MDA-MB-231 or mammary epithelial HC-11 cells. Kaempferol was demonstrated to induce sustained ERK activation concomitantly with MEK1 and ELK1 activation, and this kaempferol-induced apoptosis was suppressed by treatment with PD98059, the overexpression of a kinase-inactive ERK mutant, or ERK siRNA. Kaempferol treatment was shown to profoundly induce the generation of fluorescent DCF in the MCF-7 cells, and treatment with N-acetyl cysteine suppressed kaempferol-induced PARP cleavage. Moreover, because breast cancer is associated with increased collagen synthesis and accumulation, we utilized a collagen-based 3D culture method. Under the 3-dimensional culture condition employed herein, kaempferol treatment was shown to result in a significant reduction in cell viability, an effect which occurred in a dose-dependent manner. Compared with what was observed under conventional 2D culture condition, we observed more evident apoptotic cell death and ERK activation as the result of kaempferol treatment in a collagen-based 3D culture environment. Similar to the case of conventional 2D cultured cells, the addition of PD98059 significantly suppressed intracellular ROS production. Collectively, these results show that the sustained activation of the ERK signaling pathway is markedly involved in kaempferol-induced apoptosis of breast cancer MCF-7 cells, and that this effect is more evident under 3D culture condition.

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“…Both activate the ERK1/2 pathways but it has been proposed that the length of activation could influence the effect, with prolonged activation leading to apoptosis, and short-term to cell proliferation [108]. Sustained ERK activation has previously been demonstrated to result in inhibition of MCF-7 cell growth [109]. In vivo studies looking at olive leaf polyphenols also appear to support an anti-cancer effect.…”

The potential role of nutritional genomics tools in validating high health foods for cancer control: Broccoli as example

“…These pathways sense extracellular stresses, leading not only to the induction of Nrf2-mediated transcription (described in Fig. 3), but also to the transmission of apoptotic and cell-cycle arrest signals [31,54,55]. Cell-cycle arrest by such compounds has been suggested to occur through various mechanisms, including down-regulating the expression of the cyclin D1 protein, reducing levels of kinase cdk4, regulation of CDK inhibitors and disruption of microtubules by inhibition of tubulin polymerisation [11,56].…”

Polyphenolic extract of InsP 5-ptase expressing tomato plants reduce the proliferation of MCF-7 breast cancer cells

“…Another important naturally occurring flavonoid that is increased in our transgenic tomato lines is kaempferol. Kaempferol treatment is known to have a significant effect in reduction of cell viability in the MCF-7 cells [60]. Studies have shown that kaempferol can inhibit the cell proliferation of breast cancer cells by activation of caspase cascade in a dose-dependent manner [61].…”