Activation of Nrf2 by Sulforaphane Inhibits High Glucose-Induced Progression of Pancreatic Cancer via AMPK Dependent Signaling
Activation of Nrf2 by Sulforaphane Inhibits High Glucose-Induced Progression of Pancreatic Cancer via AMPK Dependent Signaling
复制标题
萝卜硫素激活 Nrf2 通过 AMPK 依赖性信号传导抑制高血糖诱导的胰腺癌进展。
DOI：
10.1159/000494547
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Duan, Wanxing
中科院分区：
文献类型：
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作者：
Chen, Xin;Jiang, Zhengdong;Duan, Wanxing
背景/目的：萝卜硫素（SFN）以其有效的生物活性而闻名，如抗炎和抗肿瘤作用。然而，其对胰腺癌的抗肿瘤作用仍然知之甚少。在本研究中，我们探讨了SFN对胰腺癌的治疗潜力，并揭示了潜在的机制。方法：采用Panc-1和MiaPaca-2细胞株进行体外培养。采用EdU染色、集落形成、凋亡、迁移和侵袭实验检测SFN在胰腺癌中的生物学功能。使用2 '-7'-二氯荧光素二乙酸酯（DCF-DA）荧光分析测量活性氧物质（ROS）产生。采用Western blotting和免疫荧光法检测p-AMPK和上皮-间质转化（EMT）途径相关蛋白的蛋白水平，以及核因子红细胞2相关因子2（Nrf 2）的细胞转位。采用裸鼠和转基因胰腺癌小鼠模型检测SFN对胰腺癌的治疗作用。结果如下：SFN能抑制胰腺癌细胞生长，促进细胞凋亡，抑制集落形成，并能降低胰腺癌细胞的迁移和侵袭能力。从机制上讲，SFN诱导的过量ROS产生激活AMPK信号并促进Nrf 2的易位，导致胰腺癌细胞活力抑制。AMPK信号传导的小分子抑制剂化合物C预处理逆转了Nrf 2的亚细胞易位，挽救了细胞的侵袭能力。通过裸鼠和胰腺癌转基因小鼠实验，我们证实SFN可以抑制肿瘤的进展，SFN治疗组肿瘤体积较小，肿瘤进展较慢。结论：本研究不仅阐明了SFN在正常和高糖条件下对胰腺癌的抑制作用机制，而且证实了ROS在胰腺癌进展中的双重作用。总的来说，我们的研究表明，SFN可能作为胰腺癌的潜在治疗选择。(C)2018作者（S）由S发布。Karger AG，巴塞尔
Background/Aims: Sulforaphane (SFN) is known for its potent bioactive properties, such as anti-inflammatory and anti-tumor effects. However, its anti-tumor effect on pancreatic cancer is still poorly understood. In the present study, we explored the therapeutic potential of SFN for pancreatic cancer and disclosed the underlying mechanism. Methods: Panc-1 and MiaPaca-2 cell lines were used in vitro. The biological function of SFN in pancreatic cancer was measured using EdU staining, colony formation, apoptosis, migration and invasion assays. Reactive oxygen species (ROS) production was measured using 2'-7'-Dichlorofluorescein diacetate (DCF-DA) fluorometric analysis. Western blotting and immunofluorescence were used to measure the protein levels of p-AMPK and epithelial-mesenchymal transition (EMT) pathway-related proteins, and cellular translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nude mice and transgenic pancreatic cancer mouse model were used to measure the therapeutic potential of SFN on pancreatic cancer. Results: SFN can inhibit pancreatic cancer cell growth, promote apoptosis, curb colony formation and temper the migratory and invasion ability of pancreatic cancer cells. Mechanistically, excessive ROS production induced by SFN activated AMPK signaling and promoted the translocation of Nrf2, resulting in cell viability inhibition of pancreatic cancer. Pretreatment with compound C, a small molecular inhibitor of AMPK signaling, reversed the subcellular translocation of Nrf2 and rescued cell invasion ability. With nude mice and pancreatic cancer transgenic mouse, we identified SFN could inhibit tumor progression, with smaller tumor size and slower tumor progression in SFN treatment group. Conclusion: Our study not only elucidates the mechanism of SFN-induced inhibition of pancreatic cancer in both normal and high glucose condition, but also testifies the dual-role of ROS in pancreatic cancer progression. Collectively, our research suggests that SFN may serve as a potential therapeutic choice for pancreatic cancer. (C) 2018 The Author(s) Published by S. Karger AG, Basel