Oroxylin A suppresses the development and growth of colorectal cancer through reprogram of HIF1α-modulated fatty acid metabolism.
Oroxylin A suppresses the development and growth of colorectal cancer through reprogram of HIF1α-modulated fatty acid metabolism.
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Oroxylin A通过重组HIF 1 α调节的脂肪酸代谢抑制结直肠癌的发展和生长。
DOI：
10.1038/cddis.2017.261
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发表时间：
2017-06-08
影响因子：
9
通讯作者：
Wei L
中科院分区：
文献类型：
--
作者：
Ni T;He Z;Dai Y;Yao J;Guo Q;Wei L
结肠癌的发生、发展与肥胖密切相关。因此，脂质代谢，特别是脂肪酸代谢，是结肠癌细胞能量稳态的重要组成部分，它影响着许多重要的细胞过程。黄芩苷A是黄芩中主要的生物活性类黄酮之一，具有较强的抗癌作用，但对正常组织的毒性较低。在之前的研究中，我们已经证明oroxylin A通过抑制糖酵解来重新编程癌细胞的代谢。在此，我们进一步研究了缺氧条件下oroxylin A对结肠癌细胞脂肪酸代谢的代谢调节作用。我们发现HIF1α上调脂亲蛋白、脂肪酸合成酶和甾醇调节元件结合蛋白1，下调肉碱棕榈酰基转移酶1 (CPT1)，从而促进脂质摄取和转运，增加新脂肪酸合成，抑制脂肪酸氧化。Oroxylin A灭活HCT116细胞的HIF1α和重编程脂肪酸代谢，降低细胞内脂肪酸水平，增强脂肪酸氧化。此外，oroxylin A引起的脂肪酸水平的快速下降抑制了β-cantenin的核易位，使Wnt通路失活，引起细胞周期阻滞在G2/M期。体内研究表明，高脂肪饮食增加了结肠癌的发病率，加速了肿瘤的发展。重要的是，除了对结肠癌异种移植物的生长抑制作用外，oroxylin A还具有阻止结肠癌发生和延缓原发性结肠癌进展的作用。我们的研究丰富了oroxylin A的代谢调节机制，提示oroxylin A是治疗和预防结直肠癌的有力候选药物。
The occurrence and progress of colon cancer are closely associated with obesity. Therefore, the lipid metabolism, especially fatty acid metabolism, is a significant section of energy homeostasis in colon cancer cells, and it affects many important cellular processes. Oroxylin A is one of the main bioactive flavonoids of Scutellariae radix, which has a strong anticancer effect but low toxicity to normal tissue. In previous studies, we have proved that oroxylin A reprogrammes metabolism of cancer cells by inhibiting glycolysis. Here, we further investigated the metabolism-modulating effects of oroxylin A on the fatty acid metabolism in colon cancer cells under hypoxia. We found that HIF1α upregulated adipophilin, fatty acid synthase and sterol regulatory element-binding protein 1, and downregulated carnitine palmitoyltransferase 1 (CPT1), resulting in the promoted lipid uptake and transport, increased de novo fatty acid synthesis and suppressed fatty acid oxidation. Oroxylin A inactivated HIF1α and reprogrammed fatty acid metabolism of HCT116 cells, decreasing intracellular fatty acid level and enhancing fatty acid oxidation. Furthermore, the rapid decrease of fatty acid level caused by oroxylin A inhibited the nuclear translocation of β-cantenin and inactivated the Wnt pathway, arousing cell cycle arrest in G2/M phase. In vivo studies demonstrated that high-fat diet increased the incidence of colon cancer and accelerated tumor development. Importantly, besides the growth inhibitory effects on colon cancer xenograft, oroxylin A prevented carcinogenesis and delayed progress of primary colon cancer as well. Our studies enriched the metabolic regulatory mechanism of oroxylin A, and suggested that oroxylin A was a potent candidate for the treatment and prevention of colorectal cancer.
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影响因子：
8
作者：
Semenza, G. L.
通讯作者：
Semenza, G. L.
影响因子：
168.9
作者：
Renehan, Andrew G.;Tyson, Margaret;Zwahlen, Marcel
通讯作者：
Zwahlen, Marcel
影响因子：
8.8
作者：
Mashima, T.;Seimiya, H.;Tsuruo, T.
通讯作者：
Tsuruo, T.
影响因子：
11.2
作者：
Furuta, Eiji;Okuda, Hiroshi;Kobayashi, Aya;Watabe, Kounosuke
通讯作者：
Watabe, Kounosuke
影响因子：
3.8
作者：
Havermann, Susannah;Chovolou, Yvonni;Waetjen, Wim
通讯作者：
Waetjen, Wim