Wei L, Zhou Y, Qiao C, Ni T, Li Z, You Q, Guo Q, Lu N
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
JiangSu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
Cell Death Dis. 2015 Apr 9;6(4):e1714. doi: 10.1038/cddis.2015.86.
Alterations of cellular metabolism play a central role in the development and progression of cancer. Oroxylin A, an active flavonoid of a Chinese traditional medicinal plant, was previously shown to modulate glycolysis in cancer cells. However, the mechanism by which oroxylin A regulates glycolysis is still not well defined. Here, we show that oroxylin A inhibits glycolysis in breast cancer cells via the Sirtuin 3 (SIRT3)-mediated destabilization of hypoxia-inducible factor 1α (HIF1α), which controls glycolytic gene expression. Oroxylin A promotes superoxide dismutase (SOD2) gene expression through SIRT3-regulated DNA-binding activity of FOXO3a and increases the activity of SOD2 by promoting SIRT3-mediated deacetylation. In vivo, oroxylin A inhibits the growth of transplanted human breast tumors associated with glycolytic suppression. These data indicate that oroxylin A inhibits glycolysis-dependent proliferation of breast cancer cells, through the suppression of HIF1α stabilization via SIRT3 activation, providing preclinical information for the cancer therapies of SIRT3 stimulation.
细胞代谢改变在癌症的发生和发展中起着核心作用。木犀草素A是一种中国传统药用植物的活性黄酮类化合物，先前已被证明可调节癌细胞中的糖酵解。然而，木犀草素A调节糖酵解的机制仍未明确。在此，我们表明木犀草素A通过沉默调节蛋白3（SIRT3）介导的缺氧诱导因子1α（HIF1α）的去稳定化来抑制乳腺癌细胞中的糖酵解，HIF1α控制着糖酵解基因的表达。木犀草素A通过SIRT3调节的叉头框蛋白O3a（FOXO3a）的DNA结合活性促进超氧化物歧化酶（SOD2）基因表达，并通过促进SIRT3介导的去乙酰化作用增加SOD2的活性。在体内，木犀草素A抑制与糖酵解抑制相关的人乳腺癌移植瘤的生长。这些数据表明，木犀草素A通过激活SIRT3抑制HIF1α的稳定化，从而抑制乳腺癌细胞依赖糖酵解的增殖，为SIRT3刺激的癌症治疗提供了临床前信息。
