College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
Bioorg Med Chem Lett. 2014 Jun 1;24(11):2560-4. doi: 10.1016/j.bmcl.2014.03.084. Epub 2014 Apr 3.
Among many signals to regulate hypoxia inducible factor 1α (HIF-1α), sphingosine kinase 1 (SPHK1) is also involved in various biological activities such as cell growth, survival, invasion, angiogenesis, and carcinogenesis. Thus, in the present study, molecular mechanisms of coumestrol were investigated on the SPHK1 and HIF-1α signaling pathway in hypoxic PC-3 prostate cancer cells. Coumestrol significantly suppressed SPHK1 activity and accumulation of HIF-1α in a time- and concentration-dependent manner in hypoxic PC-3 cells. In addition, coumestrol inhibited the phosphorylation status of AKT and glycogen synthase kinase-3β (GSK 3β) signaling involved in cancer metabolism. Furthermore, SPHK1 siRNA transfection, sphigosine kinase inhibitor (SKI), reactive oxygen species (ROS) enhanced the inhibitory effect of coumestrol on the accumulation of HIF-1α and the expression of pAKT and pGSK 3β in hypoxic PC-3 cells by combination index. Overall, our findings suggest that coumestrol suppresses the accumulation of HIF-1α via suppression of SPHK1 pathway in hypoxic PC-3 cells.
在调节缺氧诱导因子 1α（HIF-1α）的众多信号中，鞘氨醇激酶 1（SPHK1）也参与了各种生物活性，如细胞生长、存活、侵袭、血管生成和癌变。因此，在本研究中，研究了香豆雌酚在缺氧 PC-3 前列腺癌细胞中 SPHK1 和 HIF-1α信号通路的分子机制。香豆雌酚在缺氧 PC-3 细胞中以时间和浓度依赖的方式显著抑制 SPHK1 活性和 HIF-1α的积累。此外，香豆雌酚抑制了参与癌症代谢的 AKT 和糖原合酶激酶-3β（GSK 3β）信号的磷酸化状态。此外，SPHK1 siRNA 转染、鞘氨醇激酶抑制剂（SKI）、活性氧（ROS）通过联合指数增强了香豆雌酚对缺氧 PC-3 细胞中 HIF-1α积累和 pAKT 和 pGSK 3β表达的抑制作用。总的来说，我们的研究结果表明，香豆雌酚通过抑制缺氧 PC-3 细胞中的 SPHK1 途径抑制 HIF-1α的积累。
