Lower endogenous p53 levels and degradation of AKT protein contribute to potent suppression of the new antibiotic Xiakemycin A on tumor cells

Chen,Chuan; Jiang,Zhongke; Ou,Xiuyuan; Zhang,Huixian; Sun,Chenghang; He,Qiyang

doi:10.3892/or.2018.6380

Lower endogenous p53 levels and degradation of AKT protein contribute to potent suppression of the new antibiotic Xiakemycin A on tumor cells

Authors:
- Chuan Chen
- Zhongke Jiang
- Xiuyuan Ou
- Huixian Zhang
- Chenghang Sun
- Qiyang He
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Affiliations: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
Published online on: April 18, 2018 https://doi.org/10.3892/or.2018.6380
Pages: 3048-3054

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Abstract

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.

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