Citrus Flavone Tangeretin Inhibits CRPC Cell Proliferation by Regulating Cx26, AKT, and AR Signaling.
Citrus Flavone Tangeretin Inhibits CRPC Cell Proliferation by Regulating Cx26, AKT, and AR Signaling.
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柑橘黄酮橘皮素通过调节 Cx26、AKT 和 AR 信号传导抑制 CRPC 细胞增殖
DOI：
10.1155/2022/6422500
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Lai Y
中科院分区：
文献类型：
--
作者：
Zhang N;Wu W;Huang Y;An L;He Z;Chang Z;He Z;Lai Y
前列腺癌（PCa）的进展取决于雄激素受体（AR）的作用。因此，预防配体介导的AR活化是转移性前列腺癌的一线治疗策略。雄激素剥夺疗法（ADT）可以抑制配体与AR的结合，初步缓解PCa的进展。然而，由于PCa的适应性和AR信号的恢复，最终发展为去势抵抗性前列腺癌（CRPC）。探索能够靶向AR信号的新型膳食化合物似乎是CRPC的可行替代治疗选择。本文主要研究了柑橘类水果中含有多种类黄酮成分的化合物。首先利用网络药理学方法分析了中药中常用的橙皮的关键成分及其下游靶点。值得注意的是，我们发现橘皮中的活性成分橘皮素可以显著抑制CRPC细胞（C4-2和Du145细胞）的增殖和迁移，同时还可以协同提高CRPC细胞对抗肿瘤药物索拉非尼或顺铂的敏感性。橘子皮素还显著降低C4-2细胞中AR和AKT的表达，以及雄激素不敏感细胞系Du145中转录3信号传导和激活因子的表达。此外，橘皮素增加了connexin26 （Cx26）的表达和间隙连接功能，这可能介导顺铂或索拉非尼的旁观者效应。综上所述，本研究揭示了一种新的分子机制，即橙皮素可能通过影响Cx26/AKT/AR通路，协同增加CRPC细胞对索拉非尼和顺铂的敏感性，从而抑制CRPC细胞的增殖。
Prostate cancer (PCa) progression depends on the action of androgen receptors (AR). Therefore, preventing ligand-mediated activation of AR is the first-line treatment strategy for metastatic PCa. Androgen deprivation therapy (ADT) can inhibit ligand binding to AR and alleviate PCa progression initially. However, due to the adaptation of PCa and recovery of AR signaling, castration-resistant prostate cancer (CRPC) eventually develops. Exploring novel dietary compounds that can target AR signaling appears to be a viable alternative therapeutic option for CRPC. In the present study, compounds from the citrus fruits were focused upon, which contain various flavonoid ingredients. Key components contained within orange peel, which is frequently used in traditional Chinese medicine, and downstream targets were first analyzed using network pharmacology approach. Notably, it was found that tangeretin, an active ingredient from orange peel, can significantly inhibit CRPC cell (C4-2 and Du145 cells) proliferation and migration whilst also synergistically increasing the sensitivity of CRPC cells to anti-tumor drugs sorafenib or cisplatin. Tangeretin also significantly reduced AR and AKT expressions in C4-2 cells and signal transducer and activator of transcription 3 expression in the androgen-insensitive cell line Du145. In addition, tangeretin increased the expression of both connexin26 (Cx26) and gap junction function, which may mediate the bystander effects of cisplatin or sorafenib. Taken together, the present study revealed a novel molecular mechanism by which tangeretin may inhibit the proliferation of CRPC cells, by affecting the Cx26/AKT/AR pathway, to synergistically increase the sensitivity of CRPC cells to sorafenib and cisplatin.
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