β_2受体阻滞剂对胰腺癌细胞侵袭能力的影响及其机制

Inhibition of human pancreatic cancer by β_2-adrenergic antagonist via suppression of invasion

目的研究β2受体阻滞剂对胰腺癌细胞的增殖及侵袭转移能力的影响及其作用机制。方法β2受体特异性阻滞剂ICI118,551、广谱β受体阻断剂普萘洛尔和β1受体特异性阻滞剂美托洛尔干预胰腺癌细胞MIA PaCa-2和BxPC-3后,通过MTT分析、流式细胞术,细胞侵袭实验,Western blot和EMSA等技术阐明β2受体阻滞剂对胰腺癌侵袭能力的抑制作用,进一步检测核转录因子NF-κB和AP-1的活性及其下游相关分子VEGF、MMP-2、MMP-9和COX-2的表达。结果在优势浓度(100μmol/L)下:普萘洛尔、ICI118,551诱导胰腺癌细胞周期G1/S期阻滞和抑制增殖、侵袭效应强于美托洛尔(P<0.05);三种阻滞剂均可下调NF-κB和AP-1的活性,并降低其相关下游分子VEGF、MMP-2、MMP-9和COX-2的表达(P<0.05),普萘洛尔、ICI118,551对上述分子抑制率强于美托洛尔,对BxPC-3的抑制强于MIA PaCa-2细胞。结论β2受体阻滞剂通过下调核转录因子及其相关下游分子的表达而抑制胰腺癌细胞的增殖及侵袭转移能力。

Objective To study the effect of β2 adrenergic antagonist on the proliferation and invasiveness of pancreatic cancer cell line and its action mechanism.Methods The cancer cell proliferation was determined by MTT assay;the cancer cell invasion was detected by transwell assay;the cell cycle distribution was determined by the flow cytometry assay;the activation of NF-κB and AP-1 was measured by electrophoretic mobility shift assays;and the protein expression of VEGF,COX-2,MMP-2 and MMP-9 was analyzed by Western blot.Results β2-adrenergic antagonist ICI118551 and β1/2-adrenergic antagonist propranolol significantly induced G1/S phase arrest and apoptosis and suppressed cell invasion and proliferation as compared to β1-adrenergic antagonist metoprolol and control.In our study,β2-adrenoceptor antagonists inhibited activation of transcription factors NF-κB and AP-1.Moreover,β2-adrenoceptor antagonist therapy significantly altered VEGF,COX-2,MMP-2 and MMP-9 expressions.The effect of the ICI118,551 was stronger in BxPC-3 cell line than in MIA PaCa-2 cell line.Conclusion β2-adrenergic antagonists could suppress invasion and proliferation by inhibiting activation of NF-κB and AP-1 as well as expression of its target genes,such as MMP-9,MMP-2,VEGF and COX-2.