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Year : 2014  |  Volume : 10  |  Issue : 4  |  Page : 991-997

Carvedilol suppresses migration and invasion of malignant breast cells by inactivating Src involving cAMP/PKA and PKCδ signaling pathway

Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong, China

Correspondence Address:
Fu Qinye
The Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.137664

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Context: Carvedilol (CAR) can inhibit cell growth and induce cell apoptosis in breast cancer in vitro. But it is still not known whether CAR affects the migration and invasion of breast cancer cells. Aims: To investigate the effects of CAR on migration and invasion of breast cancer cells and its corresponding signal pathways. Settings and Design: Firstly, the invasive potential of breast cancer cells were investigated after incubation with CAR and/or norepinephrine (NE). If the invasive potential of breast cancer cells were inhibited by CAR, then the signal pathways related to migration and invasion were detected, such as Src, cyclic adenosine monohposphate (cAMP)/protein kinase A (PKA), etc. Subjects and Methods: Membrane invasion culture system (MICS) chamber was used to measure the invasive and migratory potential of breast cancer cells. Western blot analysis and small interfering RNA (siRNA) transfection experiment were employed to determine the signal pathway adopted by CAR in suppressing migration and invasion of MDA-MB-231 and MCF-7 cells. cAMP-Glo and PKCδ kinase activity assay kit were used to measure cAMP and PKCδ activity, respectively, according to the manufacturer's instructions. Statistical analysis used: Statistical differences between the mean values of control and experimental groups were determined using two-tailed, unpaired Student's t-tests. Results: CAR significantly decreased the potential of migration and invasion of breast cancer cells. CAR inhibited Src activation in MDA-MB-231 and MCF-7 cells through blocking beta or alpha adrenergic receptor (ADR), respectively. Furthermore, CAR suppressed the Src activation through different signaling pathways. Under treatment of CAR, cAMP/PKA-Src pathway was inhibited in MDA-MB-231 cells; but in MCF-7 cells, CAR mainly inhibited the PKCδ-Src pathway. Conclusions: CAR was an anti-metastatic agent, which targets Src involving cAMP/PKA or PKCδ pathway in malignant breast cells.

Abstract in Chinese

卡维地洛通过阻止Src相关cAMP/PKA和PKCδ信号通路来抑制恶性乳腺癌细胞的侵袭和迁移 摘要 背景:卡维地洛(CAR)在体外可抑制乳腺癌细胞生长并诱导细胞凋亡。但它是否影响乳腺癌细胞的侵袭和迁移仍是未知的。 目的:研究卡维地洛对乳腺癌细胞的侵袭和迁移及其相应的信号通路的影响。 背景设计:首先,评估了卡维地洛和/或去甲肾上腺素(NE)孵育后的乳腺癌细胞的侵袭能力。如果乳腺癌细胞的侵袭能力被卡维地洛抑制,就对迁移和侵袭相关的信号通路进行检测,如Src,环磷酸腺苷(cAMP)/蛋白激酶A(PKA)等。 对象和方法:膜侵袭培养系统(MIC)室用来测定乳腺癌细胞的侵袭和迁移的潜力。蛋白质印迹分析和小干扰RNA(siRNA)转染实验被用来确定卡维地洛采用的抑制MDA-MB-231和MCF-7细胞侵袭的信号通路。根据制造商的说明,用cAMP-Glo和PKCδ激酶活性检测试剂盒分别测定cAMP及PKCδ活性。 统计分析:采用双尾法测定对照组和实验组的平均值之间的差异,非配对t检验。 结果:卡维地洛明显降低乳腺癌细胞的侵袭和迁移的潜力。卡维地洛抑制MDA-MB-231和MCF-7细胞中Src的激活分别通过阻断β或α-肾上腺素能受体(ADR)。此外,卡维地洛抑制Src通过激活不同的信号通路。在卡维地洛治疗下,MDA-MB-231细胞的cAMP/PKA-Src通路被抑制;但在MCF- 7细胞,卡维地洛主要抑制PKCδ-Src通路。 结论:卡维地洛是一种抗肿瘤药,主要作用于恶性乳腺癌Src相关的cAMP/PKA 或 PKCδ信号通路。 关键词:卡维地洛,恶性乳腺细胞,迁移,信号通路,SRC

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