Berberine decelerates glucose metabolism via suppression of mTOR-dependent HIF-1α protein synthesis in colon cancer cells
Berberine decelerates glucose metabolism via suppression of mTOR-dependent HIF-1α protein synthesis in colon cancer cells
复制标题
小檗碱通过抑制结肠癌细胞中 mTOR 依赖性 HIF-1 α 蛋白合成来减缓葡萄糖代谢
DOI：
10.3892/or.2018.6318
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发表时间：
2018-05-01
期刊：
影响因子：
4.2
通讯作者：
Zhan, Yan-Yan
中科院分区：
文献类型：
--
作者：
Mao, Liyuan;Chen, Qiongyun;Zhan, Yan-Yan
过度活化的葡萄糖摄取和糖酵解代谢被认为是癌症的标志。小檗碱是一种具有肿瘤选择性抗癌作用的天然生物碱，已被证明可促进代谢组织和细胞的葡萄糖摄取。然而，小檗碱是否以及如何调节癌细胞的葡萄糖代谢仍然知之甚少。在本研究中，我们发现，小檗碱，抑制结肠癌细胞株HCT 116和KM 12 C的生长，极大地抑制葡萄糖摄取和葡萄糖代谢基因，GLUT 1，LDHA和HK 2在这两个细胞系中的转录，通过RT-qPCR评估。机制研究进一步表明，在小檗碱处理的结肠癌细胞系中，HIF-1（一种众所周知的对失调的癌细胞葡萄糖代谢至关重要的转录因子）的蛋白质表达而非mRNA转录被显著抑制。使用蛋白质印迹分析，这种调节似乎是通过蛋白质合成而不是蛋白质稳定性发生的，因为缺氧模拟物去铁胺（DFX）或蛋白酶体抑制剂MG 132对HIF-1蛋白降解的阻断不影响小檗碱的作用。此外，先前报道的调节HIF-1蛋白合成的mTOR信号传导被进一步发现被小檗碱抑制。综上所述，我们的研究结果表明小檗碱通过抑制mTOR依赖的HIF-1蛋白的合成来抑制结肠癌细胞过度的糖代谢，这不仅为小檗碱的肿瘤特异性毒性提供了新的机制，也为小檗碱治疗结肠癌的开发提供了理论依据。
Hyperactivated glucose uptake and glycolytic metabolism are considered as a hallmark of cancer. Berberine, a natural alkaloid with tumor-selective anticancer effects, has been shown to promote glucose uptake in metabolic tissues and cells. However, whether and how berberine regulates the glucose metabolism of cancer cells are still poorly understood. In the present study, we revealed that berberine, which suppressed the growth of colon cancer cell lines HCT116 and KM12C, greatly inhibited the glucose uptake and the transcription of glucose metabolic genes, GLUT1, LDHA and HK2 in these two cell lines as assessed by RT-qPCR. A mechanistic study further indicated that the protein expression but not mRNA transcription of HIF-1, a well-known transcription factor critical for dysregulated cancer cell glucose metabolism, was dramatically inhibited in berberine-treated colon cancer cell lines. Using western blot analysis, this regulation appears to occur via protein synthesis but not protein stability as blockade of HIF-1 protein degradation by hypoxia mimic desferrioxamine (DFX) or proteasome inhibitor MG132 did not affect berberine's effect. In addition, mTOR signaling previously reported to regulate HIF-1 protein synthesis was further found to be suppressed by berberine. Taken together, our results indicated that berberine inhibits overactive glucose metabolism of colon cancer cells via suppressing mTOR-depended HIF-1 protein synthesis, which provided not only a novel mechanism involved in berberine's tumor-specific toxicity but also a theoretical basis for the development of berberine for colon cancer treatment.