Bouchardatine suppresses rectal cancer in mice by disrupting its metabolic pathways via activating the SIRT1-PGC-1α-UCP2 axis
Bouchardatine suppresses rectal cancer in mice by disrupting its metabolic pathways via activating the SIRT1-PGC-1α-UCP2 axis
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Bouchardatine 通过激活 SIRT1-PGC-1 α-UCP2 轴来破坏其代谢途径，从而抑制小鼠直肠癌
DOI：
10.1016/j.ejphar.2019.04.029
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发表时间：
2019-07-05
影响因子：
5
通讯作者：
Huang, Zhi-Shu
中科院分区：
文献类型：
--
作者：
Xu, Yao-Hao;Song, Qin-Qin;Huang, Zhi-Shu
癌症代谢是癌症治疗策略的一个有吸引力的目标。本研究确定 Bouchardatine (Bou) 通过独立于细胞凋亡的周期阻滞而成为直肠癌生长的有效抑制剂。在培养的 HCT-116 直肠癌细胞中，Bou 增加了葡萄糖摄取/氧化和线粒体氧化能力。这些效应与解偶联蛋白 2 (UCP2) 的上调及其上游 Sirtuin 1 (SIRT1)/（肝激酶 B1）LKB1-（腺苷单磷酸激活蛋白激酶）AMPK 轴的激活有关。 UCP2 在 HCT-116 细胞中过表达 UCP2 证明了 UCP2 在癌症抑制作用中的关键作用，其代谢作用与 Bou 产生的代谢作用相似。有趣的是，Bou 激活的过氧化物酶体增殖物激活了受体 γ 辅激活因子 1 α (PGC-1 α)，并将其招募到 HCT-116 细胞中 UCP2 的启动子上，同时被 SIRT1 脱乙酰化（从而激活）。 SIRT1 通过 PGC-1 α-UCP2 发挥癌症抑制作用的必要性通过 SIRT1 缺陷和过度表达的 HCT-116 中对 Bou 的交互反应得到证实。尽管 SIRT1 的敲低、突变或药理学抑制都会消除 Bou 诱导的 PGC-1 α 脱乙酰/激活，但在过度表达 SIRT1 后观察到相反的效果。在小鼠中，Bou (50 mg/kg) 的给药也抑制了直肠癌的生长，这与肿瘤中 UCP2 表达和线粒体容量的增加有关。总的来说，我们的研究结果表明，Bou 通过激活以 SIRT1 作为主要靶标的 PGC-1 α-UCP2 轴来破坏癌细胞的代谢路径，从而具有治疗直肠癌的治疗潜力。
Cancer metabolism is an attractive target of the therapeutic strategy for cancer. The present study identified bouchardatine (Bou) as a potent suppressor of rectal cancer growth by cycle-arresting independent of apoptosis. In cultured HCT-116 rectal cancer cells, Bou increased glucose uptake/oxidation and capacity of mitochondrial oxidation. These effects were associated with an upregulation of uncoupling protein 2 (UCP2) and the activation of its upstream Sirtuin 1 (SIRT1)/(Liver kinase B1) LKB1- (Adenosine monophosphate-activated protein kinase) AMPK axis. The pivotal role of UCP2 in the cancer-suppressing effect was demonstrated by overexpressing UCP2 in HCT-116 cells with similar metabolic effects to those produced by Bou. Interestingly, Bou activated peroxisome proliferators activated receptor gamma coactivator 1 alpha (PGC-1 alpha) and recruited it to the promoter of UCP2 in HCT-116 cells along with deacetylation (thus activation) by SIRT1. The requirement of SIRT1 for the cancer-suppressing effect through the PGC-1 alpha-UCP2 was confirmed by the reciprocal responses to Bou in HCT-116 with defected and overexpressed SIRT1. Whereas knockdown, mutation or pharmacological inhibition of SIRT1 all abolished Bou-induced deacetylation/activation of PGC-1 alpha, the opposing effects were observed after overexpressing SIRT1. In mice, administration of Bou (50 mg/kg) also suppressed the growth of rectal cancer associated with increases the UCP2 expression and mitochondria capacity in the tumor. Collectively, our findings suggest that Bou has a therapeutic potential for the treatment of rectal cancer by disrupting the metabolic path of cancer cells via activating the PGC-1 alpha-UCP2 axis with SIRT1 as its primary target.