Quercetin suppresses the mobility of breast cancer by suppressing glycolysis through Akt-mTOR pathway mediated autophagy induction
Quercetin suppresses the mobility of breast cancer by suppressing glycolysis through Akt-mTOR pathway mediated autophagy induction
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DOI：
10.1016/j.lfs.2018.07.027
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发表时间：
2018-09-01
期刊：
影响因子：
6.1
通讯作者：
Han, Lili
中科院分区：
文献类型：
--
作者：
Jia, Lijun;Huang, Shan;Han, Lili
肿瘤转移是导致癌症患者死亡的首要因素，通过抑制糖酵解来抑制肿瘤转移是肿瘤治疗的研究重点，糖酵解是肿瘤细胞运动的主要能量供应途径。本研究旨在探讨具有生物活性的黄酮类化合物--槲皮素对肿瘤转移和细胞糖酵解的影响及其在乳腺癌进展中的作用机制。首先，跨孔侵袭实验和伤口愈合实验表明，槲皮素能有效地抑制细胞的迁移。相应的Western印迹结果显示，槲皮素处理下调了细胞迁移标志蛋白的表达，如基质金属蛋白酶2(MMP2)、MMP9和血管内皮生长因子(VEGFR)。进一步的实验表明，槲皮素通过抑制葡萄糖摄取和乳酸的产生，成功地抑制了细胞的糖酵解，并降低了糖酵解相关蛋白丙酮酸激酶M2(PKM2)、葡萄糖转运蛋白1(GLUT1)和乳酸脱氢酶A(LDHA)的水平。以上结果提示，槲皮素可能通过降低肿瘤微环境的酸性来抑制糖酵解，从而限制肿瘤细胞的迁移。此外，我们的进一步研究表明，栎素通过失活Akt-mTOR途径诱导了明显的自噬。同时，自噬抑制剂3-MA和Akt-mTOR途径诱导剂IGF-1的应用进一步证明，栎素通过Akt-mTOR途径诱导自噬，抑制细胞运动和糖酵解。体内实验还表明，栎素通过抑制p-AKT/AKT，抑制肿瘤生长和转移，抑制糖酵解，诱导自噬。综上所述，我们首次揭示了栎素通过Akt-mTOR途径介导的自噬诱导抑制细胞运动和糖酵解，从而抑制乳腺癌的进展，可能为乳腺癌的治疗提供一个潜在的治疗靶点。
Tumor metastasis is the primary factor causing death of cancer patients and it is a study emphasis in cancer treatment to suppress tumor metastasis by inhibiting glycolysis, which is the main way of energy supply for cell mobility in tumor. In the present study, we aimed to explore the effect of quercetin, a bioactive flavonoid, on tumor metastasis and cell glycolysis and its related functionary mechanism in breast cancer progression. Firstly, trans-well invasion assay and wound healing assay indicated that quercetin effectively suppressed cell mobility. The corresponding western blot revealed that quercetin treatment down-regulated the expression of cell migration marker proteins, such as matrix metalloproteinase 2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF). The further experiments exhibited that quercetin successfully blocked cell glycolysis by inhibiting the level of glucose uptake and the production of lactic acid, and also decreased the level of glycolysis-related proteins Pyruvate kinase M2 (PKM2), Glucose transporter1(GLUT1) and Lactate dehydrogenase A (LDHA). The above results revealed that quercetin might inhibit glycolysis to limit the migration of tumor cells by reducing the acidity of the tumor microenvironment. Moreover, our further investigation showed that quercetin induced obvious autophagy via inactivating the Akt-mTOR pathway. At the same time, the application of autophagy inhibitor 3-MA and Akt-mTOR pathway inducer IGF-1 further demonstrated that quercetin exerted inhibiting effect on cell mobility and glycolysis through Akt-mTOR pathway mediated autophagy induction. At last, the in vivo experiments also showed that quercetin treatment could suppress tumor growth and metastasis, inhibit glycolysis and induce autophagy through the inhibition of p-AKT/AKT. Taken together, we firstly revealed that quercetin suppressed the progression of breast cancer by inhibiting cell mobility and glycolysis through Akt-mTOR pathway mediated autophagy induction and may provide a potential therapeutic target for breast cancer treatment.