The Role Of Propranolol On Invasion And Migration Of Glioblastoma And Its Mechanism

Background:Previous studies suggest that immune status are deeply influenced by psychological stress. Chronic stress affects the immune activity of the cells via reducing the cytotoxicity of natural killer cells, reducing the T-cell immune response to stimulation, and altering cytokines reproduction. Nevertheless, The immune status of cancer patients are closely related to their treatment response and prognosis. Subsequently, chronic stress is co-related with tumor progression. Stress hormones, including epinephrine, norepinephrine (NE), cortisol, in physiological conditions maintain the volume present in the peripheral blood, until under stress can be a large number of secretion, the concentration in the peripheral blood enhance times. Recent studies have shown that stress hormones-especially norepinephrine could promote the invasion of various malignant tumors. The β-blocker, propranolol can effectively reverse the effects above. The matrix metalloproteinases (Matrix metalloproteinase) is a family of proteins, including secreted and membrane-bound protein can hydrolyze extracellular matrix such as, collagen laminin, fibronectin, and elastin, which makes local invasion of tumor cells, invasion and migration easier. Due to easy to use of the gelatin zymography experiments, MMP-2/9got the most attention. The present study showed that propranolol can inhibit the NE-induced MMPs secretion and thus reversed the induction of tumor invasion and its internal mechanism is not yet clear. The human brain glioblastoma is a mostly malignant tumor, which recurred from surgical resection area, caused by the tumor infiltration or transfering along white matter fiber bundle. The mostly important significative treatment is inhibiting their migration and invasion. Propranolol on glioblastoma invasion and migration ability are unclear.Purpose:To research the NE effects on glioma invasion and migration by propranolol, and to explore its internal mechanism; prophylactically clinical usage of propranolol could inhibit stress hormone induced tumor invasion.Methods:The human glioblatoma cell lines U87,U251,T98G was cultured in Dulbecco’s modified Eagle’s medium(DMEM) containing10%fetal bovine serum(FBS). The group of cells exposed to various concentration of NE (0.1～10μmol/L) was defined as study group; The group of cells exposed to propranolol (1nmol/L) after they were exposed to high concentration of NE(10μmol/L) was defined as propranolol antagonized group. The group of cells maintained by serum free DMEM was defined as control group. RT-PCR was performed to determine whetherp-receptors expressed in glioma cell lines. Transwell was performed to assess invasion and migration ability. MTT assay was utilized to evaluate the tumors’ proliferational ability. Zymography was performed to determine MMP-2secretion and activation. Western Blot was performed to evaluate ERK and MMP-2. Immunofluorescence was performed to observe cytoskeleton.Results:Three glioblastoma cell lines, T98G, U251, U87are all express β1and β2receptors. NE had no significant effect on glioma cell migration; NE does not cause significant changes in glioma cell cytoskeleton; NE value no significant impact on cell proliferation; Compared with the control group, NE can dose-dependently significantly promote the invasive ability of glioma cells (P<0.05):NE can dose-dependently significantly promote the secretory activity of MMP-2glioma cells; NE can significantly enhance the glioma cell ERK signaling pathway activity; propranolol (1nmol/L), can promote the effect of NE in the reversal; increased doses of U1026can inhibit NE-induced MMP-2secretion activity. Conclusion:NE is able to promote invasion of glioblastoma by increasing MMP-2secretion and activation via activating ERK signaling pathway, Propranolol can inhibitor NE induced glioblastoma invasion.