Norepinephrine attenuates CXCR4 expression and the corresponding invasion of MDA-MB-231 breast cancer cells via β2-adrenergic receptors

L.-P. Wang, J. Jin, F.-F. Lv, J. Cao, J. Zhang, B.-Y. Wang, Z.-M. Shao, X.-C. Hu, Z.-H. Wang

Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. iamprofwang@163.com

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• Oncology

OBJECTIVE: The growing evidence from laboratory and clinical studies has shown that the stress hormone, norepinephrine, and chronic stress promote tumor progression in a variety of tumor types. Chemokines and chemokine receptors have been shown to play a pivotal role in tumor progression. Recently, norepinephrine was reported to have a significant effect on macrophage migration by altering the expression of the chemokine receptor CCR2.

MATERIALS AND METHODS: We investigated whether chemokines and their receptors are involved in the effects of norepinephrine on breast cancer. First, we used microarray analyses to detect the alteration of 128 chemotactically relevant genes after MDA-MB-231 cells were treated for 12 h with 100 μM norepinephrine. The CXCR4 gene demonstrated the greatest response to norepinephrine treatment, with a reduction of transcription of 95.7%, and was the focus of subsequent investigations. Real-time reverse transcription-PCR was used to determine the level of CXCR4 transcription after treatment with norepinephrine at various concentrations and for different durations.

RESULTS: The results revealed that norepinephrine reduced CXCR4 transcription in a dose-dependent manner. Norepinephrine was also found to exert a negative effect on CXCR4 translational expression, as evidenced by a 44 ± 1.7% reduction in expression after a 12-h treatment with 10 µM norepinephrine. A Matrigel assay demonstrated a 51.3 ± 9.1% reduction in the number of MDA-MB-231 cells driven to migrate by CXCR4. Finally, we found the specific β2-adrenergic antagonist, ICI 118,551, eliminated the impact of norepinephrine on CXCR4 expression.

CONCLUSIONS: Norepinephrine attenuates CXCR4 expression and the corresponding invasion of MDA-MB-231 tumor cells via the β2-adrenergic receptor. The complexity of the β2-adrenergic receptor signaling pathway might contribute to these unexpected observations in our research, and this justifies further investigation into the intricate mechanisms involved.

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