1. Academic Validation
  2. Quercetin-3-O-glucuronide inhibits noradrenaline-promoted invasion of MDA-MB-231 human breast cancer cells by blocking β₂-adrenergic signaling

Quercetin-3-O-glucuronide inhibits noradrenaline-promoted invasion of MDA-MB-231 human breast cancer cells by blocking β₂-adrenergic signaling

  • Arch Biochem Biophys. 2014 Sep 1;557:18-27. doi: 10.1016/j.abb.2014.05.030.
Shunsuke Yamazaki 1 Noriyuki Miyoshi 2 Kyuichi Kawabata 3 Michiko Yasuda 2 Kayoko Shimoi 4
Affiliations

Affiliations

  • 1 Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
  • 2 Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
  • 3 Department of Bioscience, Fukui Prefectural University, 4-1-1 Matsuoka Kenjojima, Eiheiji-cho, Yoshida-gun, Fukui 910-1195, Japan.
  • 4 Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan; Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: shimoi@u-shizuoka-ken.ac.jp.
Abstract

Endogenous catecholamines such as adrenaline (A) and noradrenaline (NA) are released from the adrenal gland and sympathetic nervous system during exposure to stress. The adrenergic system plays a central role in stress signaling, and excessive stress was found to be associated with increased production of Reactive Oxygen Species (ROS). Overproduction of ROS induces oxidative damage in tissues and causes the development of diseases such as Cancer. In this study, we investigated the effects of quercetin-3-O-glucuronide (Q3G), a circulating metabolite of quercetin, which is a type of natural flavonoid, on the catecholamine-induced β2-adrenergic receptor (β2-AR)-mediated response in MDA-MB-231 human breast Cancer cells expressing β2-AR. Treatment with A or NA at concentrations above 1μM generated significant levels of ROS, and NA treatment induced the gene expression of heme oxygenase-1 (HMOX1), and matrix metalloproteinase-2 (MMP-2) and -9 (MMP9). Inhibitors of p38 MAP kinase (SB203580), cAMP-dependent protein kinase (PKA) (H-89), activator protein-1 (AP-1) transcription factor (SR11302), and NF-κB and AP-1 (Tanshinone IIA) decreased MMP2 and MMP9 gene expression. NA also enhanced cAMP induction, Ras activation and phosphorylation of ERK1/2. These results suggested that the cAMP-PKA, MAPK, and ROS-NF-κB pathways are involved in β2-AR signaling. Treatment with 0.1μM Q3G suppressed ROS generation, cAMP and Ras activation, phosphorylation of ERK1/2 and the expression of HMOX1, MMP2, and MMP9 genes. Furthermore, Q3G (0.1μM) suppressed invasion of MDA-MB-231 breast Cancer cells and MMP-9 induction, and inhibited the binding of [(3)H]-NA to β2-AR. These results suggest that Q3G may function to suppress invasion of breast Cancer cells by controlling β2-adrenergic signaling, and may be a dietary chemopreventive factor for stress-related breast Cancer.

Keywords

Invasion; MDA-MB-231; MMP; Noradrenaline; Quercetin-3-O-glucuronide; ROS; β(2)-Adrenergic signaling.

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