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DHS (trans−4,4′-dihydroxystilbene) suppresses DNA replication and tumor growth by inhibiting RRM2 (ribonucleotide reductase regulatory subunit M2)

Oncogene volume 38, pages 2364–2379 (2019)Cite this article

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Abstract

DNA replication machinery is responsible for accurate and efficient duplication of the chromosome. Since inhibition of DNA replication can lead to replication fork stalling, resulting in DNA damage and apoptotic death, inhibitors of DNA replication are commonly used in cancer chemotherapy. Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the biosynthesis of deoxyribonucleoside triphosphates (dNTPs) that are essential for DNA replication and DNA damage repair. Gemcitabine, a nucleotide analog that inhibits RNR, has been used to treat various cancers. However, patients often develop resistance to this drug during treatment. Thus, new drugs that inhibit RNR are needed to be developed. In this study, we identified a synthetic analog of resveratrol (3,5,4′-trihydroxy-trans-stilbene), termed DHS (trans−4,4′-dihydroxystilbene), that acts as a potent inhibitor of DNA replication. Molecular docking analysis identified the RRM2 (ribonucleotide reductase regulatory subunit M2) of RNR as a direct target of DHS. At the molecular level, DHS induced cyclin F-mediated down-regulation of RRM2 by the proteasome. Thus, treatment of cells with DHS reduced RNR activity and consequently decreased synthesis of dNTPs with concomitant inhibition of DNA replication, arrest of cells at S-phase, DNA damage, and finally apoptosis. In mouse models of tumor xenografts, DHS was efficacious against pancreatic, ovarian, and colorectal cancer cells. Moreover, DHS overcame both gemcitabine resistance in pancreatic cancer and cisplatin resistance in ovarian cancer. Thus, DHS is a novel anti-cancer agent that targets RRM2 with therapeutic potential either alone or in combination with other agents to arrest cancer development.

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Acknowledgements

This work was partially supported by funding from the National Institutes of Health (CA177898 and CA184717 to WZ). WZ was supported by a Research Scholar Grant, RSG-13–214–01-DMC from the American Cancer Society.

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  1. These authors contributed equally: Chi-Wei Chen, Yongming Li

Authors and Affiliations

  1. Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Chi-Wei Chen, Yongming Li, Wei Zhou, Yunxiao Meng, Zongzhu Li, Yi Zhang, Jing Sun & Wenge Zhu

  2. GW Cancer Center, The George Washington University, Washington, DC, USA

    Chi-Wei Chen, Wei Zhou, Yunxiao Meng, Zongzhu Li, Yi Zhang, Jing Sun & Wenge Zhu

  3. College of Basic Medical Sciences, Dalian Medical University, Dalian, China

    Yongming Li

  4. City of Hope National Medical Center, Duarte, CA, USA

    Shuya Hu & Yun Yen

  5. Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    Wei Zhou

  6. State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, China

    Zhou Bo

  7. National Institute of Child Health and Human Development, Bethesda, MD, USA

    Melvin L. DePamphilis

  8. Department of Medical Sciences, Hackensack Meridian School of Medicine at Seton Hall University, South Orange, NJ, USA

    Zhiyong Han

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Chen, CW., Li, Y., Hu, S. et al. DHS (trans−4,4′-dihydroxystilbene) suppresses DNA replication and tumor growth by inhibiting RRM2 (ribonucleotide reductase regulatory subunit M2). Oncogene 38, 2364–2379 (2019). https://doi.org/10.1038/s41388-018-0584-6

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