Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
Oncol Rep. 2018 Jun;39(6):3048-3054. doi: 10.3892/or.2018.6380. Epub 2018 Apr 18.
Xiakemycin A (XKA), a new pyranonaphthoquinone antibiotic, is isolated from the fermentation broth of Streptomyces sp. CC8-201. It exerts potent suppression of cell proliferation on some types of tumor cells. In the present study, its underlying mechanism on tumor cells has been investigated. In contrast to the specific AKT inhibitor triciribine hydrate, XKA demonstrated a weak inhibition of the AKT kinase activity in vitro. Knockdown of AKT protein levels reduced XKA-inhibitory action on prostate carcinoma PC-3 cells. Degradation of AKT protein was markedly observed in the XKA-treated PC-3 cells in comparison with triciribine hydrate treatment. There was no typical apoptosis induced by XKA in PC-3 cells. The propidium iodide-stained cells increased concentration-dependently when the cells were treated with XKA. Degradation of apoptosis-related proteins, such as p53 and PARP-1, was also detected in the XKA-treated PC-3 cells. Knockdown of p53 protein levels potentiated XKA action on non-small lung cancer A549 cells. Collectively, the mechanism of XKA potent inhibition was due to degradation of AKT protein and low endogenous p53 levels. As a leading compound, new derivatives based on XKA will be developed to precisely treat tumor cells which have high AKT and low p53 protein levels.
夏克霉素 A（XKA）是一种从链霉菌 sp. CC8-201 的发酵液中分离得到的新型吡喃萘醌类抗生素，对某些类型的肿瘤细胞具有很强的抑制增殖作用。本研究探讨了其对肿瘤细胞的作用机制。与 AKT 激酶特异性抑制剂曲克芦丁水合物相比，XKA 对 AKT 激酶活性的体外抑制作用较弱。AKT 蛋白水平的敲低降低了 XKA 对前列腺癌 PC-3 细胞的抑制作用。与曲克芦丁水合物处理相比，XKA 处理的 PC-3 细胞中明显观察到 AKT 蛋白的降解。XKA 处理 PC-3 细胞未诱导典型的细胞凋亡。用 XKA 处理细胞时，碘化丙啶染色的细胞浓度依赖性增加。凋亡相关蛋白如 p53 和 PARP-1 的降解也在 XKA 处理的 PC-3 细胞中检测到。p53 蛋白水平的敲低增强了 XKA 对非小细胞肺癌 A549 细胞的作用。总之，XKA 强烈抑制的机制是由于 AKT 蛋白的降解和低内源性 p53 水平。作为先导化合物，将基于 XKA 的新型衍生物开发用于精确治疗 AKT 蛋白水平高和 p53 蛋白水平低的肿瘤细胞。
