The cannabinoid WIN 55,212-2 prevents neuroendocrine differentiation of LNCaP prostate cancer cells.
The cannabinoid WIN 55,212-2 prevents neuroendocrine differentiation of LNCaP prostate cancer cells.
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DOI：
10.1038/pcan.2016.19
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发表时间：
2016-09
影响因子：
4.8
通讯作者：
Díaz-Laviada I
中科院分区：
文献类型：
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作者：
Morell C;Bort A;Vara D;Ramos-Torres A;Rodríguez-Henche N;Díaz-Laviada I
神经内分泌（NE）分化是前列腺癌的一个共同特征，与疾病进展加速和临床结局不良相关。目前，还没有治疗这种侵袭性前列腺癌的方法。本研究的目的是确定大麻素WIN 55，212 -2（WIN，一种非选择性大麻素CB 1和CB 2受体激动剂）对前列腺癌细胞NE分化的影响。前列腺癌LNCaP细胞的NE分化通过血清剥夺或通过与白细胞介素-6孵育6天来诱导。NE标记物和信号蛋白的水平通过蛋白质印迹法测定。大麻素受体的水平通过定量PCR测定。通过药理学抑制和小干扰RNA研究了信号级联的参与。分化的LNCaP细胞表现出神经突生长，并增加了典型NE标志物神经元特异性烯醇化酶和βIII微管蛋白（βIII Tub）的表达。用3 μM WIN处理抑制LNCaP细胞的NK分化。大麻素WIN下调PI 3 K/Akt/mTOR信号通路，导致NE分化抑制。此外，AMP激活的蛋白激酶（AMPK）的激活观察到在WIN-treated细胞，这与NE标志物的表达减少。我们的研究结果还表明，在NE分化的大麻素受体CB 1和CB 2的表达显着下降。总之，我们证明PI 3 K/Akt/AMPK可能是调节前列腺癌NE分化的重要轴，其被大麻素WIN阻断，指出大麻素对NE前列腺癌的治疗潜力。
Neuroendocrine (NE) differentiation represents a common feature of prostate cancer and is associated with accelerated disease progression and poor clinical outcome. Nowadays, there is no treatment for this aggressive form of prostate cancer. The aim of this study was to determine the influence of the cannabinoid WIN 55,212-2 (WIN, a non-selective cannabinoid CB1 and CB2 receptor agonist) on the NE differentiation of prostate cancer cells. NE differentiation of prostate cancer LNCaP cells was induced by serum deprivation or by incubation with interleukin-6, for 6 days. Levels of NE markers and signaling proteins were determined by western blotting. Levels of cannabinoid receptors were determined by quantitative PCR. The involvement of signaling cascades was investigated by pharmacological inhibition and small interfering RNA. The differentiated LNCaP cells exhibited neurite outgrowth, and increased the expression of the typical NE markers neuron-specific enolase and βIII tubulin (βIII Tub). Treatment with 3 μM WIN inhibited NK differentiation of LNCaP cells. The cannabinoid WIN downregulated the PI3K/Akt/mTOR signaling pathway, resulting in NE differentiation inhibition. In addition, an activation of AMP-activated protein kinase (AMPK) was observed in WIN-treated cells, which correlated with a decrease in the NE markers expression. Our results also show that during NE differentiation the expression of cannabinoid receptors CB1 and CB2 dramatically decreases. Taken together, we demonstrate that PI3K/Akt/AMPK might be an important axis modulating NE differentiation of prostate cancer that is blocked by the cannabinoid WIN, pointing to a therapeutic potential of cannabinoids against NE prostate cancer.