Carnosol, a Dietary Diterpene, Displays Growth Inhibitory Effects in Human Prostate Cancer PC3 Cells Leading to G2-Phase Cell Cycle Arrest and Targets the 5′-AMP-Activated Protein Kinase (AMPK) Pathway
Carnosol, a Dietary Diterpene, Displays Growth Inhibitory Effects in Human Prostate Cancer PC3 Cells Leading to G2-Phase Cell Cycle Arrest and Targets the 5′-AMP-Activated Protein Kinase (AMPK) Pathway
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DOI：
10.1007/s11095-008-9552-0
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发表时间：
2008-09-01
影响因子：
3.7
通讯作者：
Mukhtar, Hasan
中科院分区：
文献类型：
--
作者：
Johnson, Jeremy J.;Syed, Deeba N.;Mukhtar, Hasan
目的。本研究检测了卡诺醇在人前列腺癌PC3细胞中的抗癌作用及其在调节与致癌相关的多个信号通路中的作用。用卡诺醇处理PC3细胞，用流式细胞仪、蛋白质芯片和蛋白质印迹分析鉴定卡诺醇靶向的信号转导通路。采用四甲基偶氮唑盐比色法，我们发现卡诺醇(10-70muM)以时间和剂量依赖的方式降低细胞存活率。进一步的流式细胞仪分析和生化分析证实细胞周期停滞于G(2)期。为了建立更精确的机制，我们进行了一组蛋白质阵列，评估了参与细胞信号通路的638种蛋白质。该蛋白质阵列确定了5‘-AMP激活的蛋白激酶(AMPK)，这是一种参与调节细胞能量平衡的丝氨酸/苏氨酸蛋白激酶，是一个潜在的靶点。与癌症抑制相一致的进一步下游效应包括对mTOR/HSP70S6k/4E-BP1通路的调控。此外，我们还发现卡诺醇以剂量依赖的方式靶向PI3K/Akt通路。这些结果表明，肌醇以包括AMPK通路在内的多种信号通路为靶点。卡诺醇在体外抑制前列腺癌的能力表明，卡诺醇可能是一种治疗前列腺癌的新药物。
Purpose. This study examines the anti-cancer effect of carnosol in human prostate cancer PC3 cells and its role in modulating multiple signaling pathways associated with carcinogenesis.Methods. PC3 cells were treated with carnosol and were evaluated using a flow cytometry, a protein array and Western blot analysis to identify signaling pathways targeted by carnosol.Results. Using an MTT assay we found that carnosol (10-70 mu M) decreases cell viability in a time and dose-dependent manner. Further analysis using flow cytometry as well as biochemical analysis identified G(2)-phase cell cycle arrest. To establish a more precise mechanism, we performed a protein array that evaluated 638 proteins involved in cell signaling pathways. The protein array identified 5'-AMP-activated protein kinase (AMPK), a serine/threonine protein kinase involved in the regulation of cellular energy balance as a potential target. Further downstream effects consistent with cancer inhibition included the modulation of the mTOR/HSP70S6k/4E-BP1 pathway. Additionally, we found that carnosol targeted the PI3K/Akt pathway in a dose dependent manner.Conclusions. These results suggest that carnosol targets multiple signaling pathways that include the AMPK pathway. The ability of carnosol to inhibit prostate cancer in vitro suggests carnosol may be a novel agent for the management of PCa.