Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
Guangzhou First People's Hospital, School of Medicine and Institutes for Life Sciences, South China University of Technology, Guangzhou 510006, China.
Cells. 2019 May 10;8(5):439. doi: 10.3390/cells8050439.
HIF-1 serves as an important regulator in cell response to hypoxia. Due to its key role in promoting tumor survival and progression under hypoxia, HIF-1 has become a promising target of cancer therapy. Thus far, several HIF-1 inhibitors have been identified, most of which are from synthesized chemical compounds. Here, we report that ALM (ActinoactoMycin, a compound extracted from metabolites of , exhibits inhibitory effect on HIF-1α. Mechanistically, we found that ALM inhibited the translation of HIF-1α protein by suppressing mTOR signaling activity. Treatment with ALM induced cell apoptosis and growth inhibition of cancer cells both in vitro and in vivo in a HIF-1 dependent manner. More interestingly, low dose of ALM treatment enhanced the anti-tumor effect of Everolimus, an inhibitor of mTOR, suggesting its potential use in combination therapy of tumors, especially solid tumor patients. Thus, we identified a novel HIF-1α inhibitor from the metabolites of which shows promising anti-cancer potential.
HIF-1 作为细胞对缺氧反应的重要调节剂。由于其在促进缺氧下肿瘤存活和进展中的关键作用，HIF-1 已成为癌症治疗的有前途的靶点。迄今为止，已经鉴定出几种 HIF-1 抑制剂，其中大多数来自合成的化学化合物。在这里，我们报告说，ALM（放线菌素，一种从 的代谢产物中提取的化合物）对 HIF-1α 具有抑制作用。在机制上，我们发现 ALM 通过抑制 mTOR 信号活性来抑制 HIF-1α 蛋白的翻译。ALM 的处理以依赖于 HIF-1 的方式在体外和体内诱导癌细胞的细胞凋亡和生长抑制。更有趣的是，低剂量的 ALM 处理增强了 mTOR 抑制剂 Everolimus 的抗肿瘤作用，表明其在肿瘤联合治疗中的潜在用途，特别是在实体瘤患者中。因此，我们从 的代谢产物中鉴定出一种新型的 HIF-1α 抑制剂，具有有前途的抗癌潜力。
