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

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

doi:10.26599/FSHW.2022.9250241

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

Xiaolu Ma^{^a^,^b^,^c^,¹}, Fei Yang^{^b^,¹}, Ke Ma^{^d^,¹}, Hongyan Shen^{^b^,¹}, Junjie Han^{^d}, Kai Wang^{^d}, Yeran Yang^{^b}, Jiawei Zhu^{^b}, Ruiyuan An^{^b}, Qilin Wang^{^b}, Tie-Shan Tang^{^c^,^e^,^f}, Bo Zhou^{^b}(), Hongwei Liu^{^d}(), Caixia Guo^{^b}

()

College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan 030024, China

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

State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China

Institute of Microbiology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China

Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China

University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China

¹ Authors contributes equally to this work.

Peer review under responsibility of Tsinghua University Press.

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Abstract

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 Polη and 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.

Keywords

Ganoderma boninenseGanoboninketal C Cisplatin chemotherapy Translesion DNA synthesis

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References

[1]

D.W. Shen, L.M. Pouliot, M.D. Hall, et al., Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes, Pharmacol. Rev. 64(3) (2012) 706-721. http://dx.doi.org/10.1124/pr.111.005637.

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

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