Targeting aerobic glycolysis and HIF-1alpha expression enhance imiquimod-induced apoptosis in cancer cells.
Targeting aerobic glycolysis and HIF-1alpha expression enhance imiquimod-induced apoptosis in cancer cells.
复制标题
DOI：
10.18632/oncotarget.1734
复制
发表时间：
2014-03-15
期刊：
影响因子：
--
通讯作者：
Shieh JJ
中科院分区：
文献类型：
--
作者：
Huang SW;Kao JK;Wu CY;Wang ST;Lee HC;Liang SM;Chen YJ;Shieh JJ
肿瘤细胞依靠有氧糖酵解来维持不受约束的细胞生长和增殖。咪喹莫特（IMQ）是一种合成的toll样受体（TLR） 7/8配体，通过直接诱导癌细胞死亡和/或间接激活针对肿瘤细胞的细胞免疫应答来发挥抗肿瘤作用。然而，IMQ是否调节葡萄糖代谢途径仍不清楚。在这项研究中，我们证明了IMQ可以通过ROS介导的STAT3和akt依赖性途径，在转录和翻译水平上上调HIF-1α的表达，而不依赖于TLR7/8信号通路，从而促进有氧糖酵解。HIF-1α的基因沉默不仅抑制了imq诱导的有氧糖酵解，而且由于ATP和Mcl-1的更快消耗，使细胞对imq诱导的凋亡敏感。此外，葡萄糖类似物2-DG和破坏HIF-1α蛋白稳定的Hsp90抑制剂17-AAG在体外与IMQ协同诱导肿瘤细胞凋亡，并在体内显著抑制肿瘤生长。因此，我们假设IMQ诱导的HIF-1α和有氧糖酵解的上调是对IMQ治疗产生的代谢应激的保护性反应，因此，与HIF-1α和/或糖酵解抑制剂共同治疗可能是一种有用的治疗策略，可以在临床环境中增强IMQ的抗肿瘤作用。
Tumor cells rely on aerobic glycolysis to maintain unconstrained cell growth and proliferation. Imiquimod (IMQ), a synthetic Toll-like receptor (TLR) 7/8 ligand, exerts anti-tumor effects directly by inducing cell death in cancer cells and/or indirectly by activating cellular immune responses against tumor cells. However, whether IMQ modulates glucose metabolism pathways remains unclear. In this study, we demonstrated that IMQ can enhance aerobic glycolysis by up-regulating HIF-1α expression at the transcriptional and translational levels via ROS mediated STAT3- and Akt-dependent pathways, independent of TLR7/8 signaling. The genetic silencing of HIF-1α not only repressed IMQ-induced aerobic glycolysis but also sensitized cells to IMQ-induced apoptosis due to faster ATP and Mcl-1 depletion. Moreover, the glucose analog 2-DG and the Hsp90 inhibitor 17-AAG, which destabilizes the HIF-1α protein, synergized with IMQ to induce tumor cell apoptosis in vitro and significantly inhibited tumor growth in vivo. Thus, we hypothesize that the IMQ-induced up-regulation of HIF-1α and aerobic glycolysis is a protective response to the metabolic stress generated by IMQ treatment, and thus, co-treatment with inhibitors of HIF-1α and/or glycolysis may be a useful therapeutic strategy to enhance the anti-tumor effects of IMQ in clinical settings.
登录
查看更多内容
影响因子：
11.2
作者：
Ibrahim, NO;Hahn, T;Katschinski, DM
通讯作者：
Katschinski, DM
影响因子：
4.6
作者：
Huang, Shi-Wei;Chang, Chia-Che;Shieh, Jeng-Jer
通讯作者：
Shieh, Jeng-Jer
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
5.7
作者：
Hu, Yongzhen;Kirito, Keita;Komatsu, Norio
通讯作者：
Komatsu, Norio
影响因子：
4.1
作者：
Frede, Stilla;Stockmann, Christian;Fandrey, Joachim
通讯作者：
Fandrey, Joachim