Ganoboninketal C from Ganoderma boninense improves the efficacy of CDDP-based chemotherapy through inhibiting translesion DNA synthesis  

作　　者：Xiaolu Ma Fei Yang Ke Ma Hongyan Shen Junjie Han Kai Wang Yeran Yang Jiawei Zhu Ruiyuan An Qilin Wang Tie-Shan Tang Bo Zhou Hongwei Liu Caixia Guo 

机构地区：[1]College of Biomedical Engineering,Taiyuan University of Technology,Taiyuan 030024,China [2]CAS Key Laboratory of Genomics and Precision Medicine,Beijing Institute of Genomics/China National Center for Bioinformation,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Beijing 100101,China [3]State Key Laboratory of Membrane Biology,Institute of Zoology,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Beijing 100101,China [4]Institute of Microbiology,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Beijing 100101,China [5]Beijing Institute for Stem Cell and Regenerative Medicine,Beijing 100101,China [6]University of Chinese Academy of Sciences,Chinese Academy of Sciences,Beijing 100101,China

出　　处：《Food Science and Human Wellness》2024年第5期2982-2992,共11页食品科学与人类健康（英文）

基　　金：supported by National Key Research and Development Program of China(2018YFA0108500);NSFC82341006,81673334,31970740,31801144,31800684 and 31701227;Natural Science Foundation of Beijing(IS23071);Postdoctoral Research Foundation of China(2021M703206);Natural Science Foundation of Shanxi Province(202203021211155);the State Key Laboratory of Membrane Biology.

摘　　要：Translesion DNA synthesis(TLS)can bypass DNA lesions caused by chemotherapeutic drugs,which usually result in drug resistance.Given its key role in mutagenesis and cell survival after DNA damage,inhibition of the TLS pathway has emerged as a potential target for improving the efficacy of DNA-damaging agents such as cisplatin(CDDP),a widely used anticancer agent.Unfortunately,few suitable natural TLS inhibitors have been reported.Here,we found that a triterpenoid compound Ganoboninketal C(26-3)from Ganoderma boninense,a traditional Chinese medicine,can impair CDDP-induced TLS polymerase eta(Polη)focus formation,PCNA monoubiquitination as well as mutagenesis.Moreover,26-3 can significantly sensitize tumor cells to CDDP killing and reduce the proportion of cancer stem cells in AGS and promote apoptosis after CDDP exposure.Interestingly,26-3 can also sensitize tumor cells to Gefitinib therapy.Mechanistically,through RNA-seq analysis,we found that 26-3 could abrogate the CDDP-induced upregulation of Polηand PIDD(p53-induced protein with a death domain),2 known factors promoting TLS pathway.Furthermore,we found that activating transcription factor 3 is a potential novel TLS modulator.Taken together,we have identified a natural TLS inhibitor 26-3,which can be potentially used as an adjuvant to improve clinical efficacy.

关 键 词：Ganoderma boninense Ganoboninketal C Cisplatin chemotherapy Translesion DNA synthesis 

分 类 号：TQ460.1[化学工程—制药化工] R285[医药卫生—中药学]