Piperlongumine induces rapid depletion of the androgen receptor in human prostate cancer cells.
Piperlongumine induces rapid depletion of the androgen receptor in human prostate cancer cells.
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DOI：
10.1002/pros.22535
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发表时间：
2013-01
期刊：
影响因子：
2.8
通讯作者：
Kolenko, Vladimir M.
中科院分区：
文献类型：
--
作者：
Golovine, Konstantin V.;Makhov, Peter B.;Teper, Ervin;Kutikov, Alexander;Canter, Daniel;Uzzo, Robert G.;Kolenko, Vladimir M.
雄激素受体（AR）信号转导被认为是前列腺癌发生的驱动力，其调节是前列腺癌（PC）预防和治疗的逻辑靶点。天然产物是药物开发中最稳定的小分子来源。在这项研究中，我们调查的功能影响piperlongumine（PL），一种天然存在的生物碱长辣椒（Piper longum），PC细胞中的AR表达，并描绘其作用机制。Western blotting和荧光素酶报告基因检测AR的表达和转录活性。CellTiter Blue测定用于定量细胞增殖。通过用活性氧指示剂CM-H2 DCFDA染色细胞，然后进行流式细胞术分析来检查活性氧（ROS）的产生。我们的实验结果表明，PL通过蛋白酶体介导的ROS依赖性机制快速降低PC细胞中的AR蛋白水平。此外，PL有效地耗尽了缺乏配体结合结构域的修饰的AR，揭示了表达突变的组成型活性AR的前列腺癌治疗方法的新范例。重要的是，PL在低微摩尔浓度下有效地耗尽前列腺癌细胞中的AR，同时对AR转录活性和前列腺癌细胞增殖产生显著的抑制作用。我们的研究首次表明，PL诱导前列腺癌细胞中AR的快速消耗。因此，PL可能为预防和治疗前列腺恶性肿瘤提供新的机会。
Androgen receptor (AR) signaling is regarded as the driving force in prostate carcinogenesis, and its modulation represents a logical target for prostate cancer (PC) prevention and treatment. Natural products are the most consistent source of small molecules for drug development. In this study, we investigate the functional impact of piperlongumine (PL), a naturally occurring alkaloid present in the Long pepper (Piper longum), on AR expression in PC cells and delineate its mechanism of action. Expression and transcriptional activity of AR was examined by Western blotting and luciferase reporter assay, respectively. CellTiter Blue assay was utilized to quantify cell proliferation. Reactive oxygen species (ROS) generation was examined by staining cells with a ROS indicator CM-H2DCFDA, followed by flow cytometry analysis. The results of our experiments demonstrate that PL rapidly reduces AR protein levels in PC cells via proteasome-mediated ROS-dependent mechanism. Moreover, PL effectively depletes a modified AR lacking the ligand-binding domain, shedding light on a new paradigm in the treatment approach to prostatic carcinoma that expresses mutated constitutively active AR. Importantly, PL effectively depletes AR in prostate cancer cells at low micromolar concentrations, while concurrently exerting a significant inhibitory effect on AR transcriptional activity and proliferation of prostate cancer cells. Our investigation demonstrates for the first time that PL induces rapid depletion of the AR in prostate cancer cells. As such, PL may afford novel opportunities for both prevention and treatment of prostatic malignancy.
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影响因子：
12.4
作者：
Makhov, P.;Golovine, K.;Uzzo, R. G.;Rothman, J.;Crispen, P. L.;Shaw, T.;Scoll, B. J.;Kolenko, V. M.
通讯作者：
Kolenko, V. M.
影响因子：
1.2
作者：
Krizova, L.;Watzkova, J.;Buchta, M.
通讯作者：
Buchta, M.
DOI：
10.1158/1078-0432.ccr-08-0455
发表时间：
2008-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Golovine K;Makhov P;Uzzo RG;Shaw T;Kunkle D;Kolenko VM
通讯作者：
Kolenko VM
影响因子：
6
作者：
Holzbeierlein, J;Lal, P;Gerald, WL
通讯作者：
Gerald, WL
影响因子：
3.8
作者：
Pereira, Claudia V.;Machado, Nuno G.;Oliveira, Paulo J.
通讯作者：
Oliveira, Paulo J.