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The thioredoxin system determines CHK1 inhibitor sensitivity via redox-mediated regulation of ribonucleotide reductase activity

Author

Listed:
  • Chandra Bhushan Prasad

    (The Ohio State University)

  • Adrian Oo

    (Emory University)

  • Yujie Liu

    (The Ohio State University)

  • Zhaojun Qiu

    (The Ohio State University)

  • Yaogang Zhong

    (The Ohio State University
    The Ohio State University)

  • Na Li

    (The Ohio State University)

  • Deepika Singh

    (The Ohio State University)

  • Xiwen Xin

    (The Ohio State University)

  • Young-Jae Cho

    (Emory University)

  • Zaibo Li

    (College of Medicine)

  • Xiaoli Zhang

    (The Ohio State University)

  • Chunhong Yan

    (Augusta University)

  • Qingfei Zheng

    (The Ohio State University
    The Ohio State University)

  • Qi-En Wang

    (The Ohio State University)

  • Deliang Guo

    (The Ohio State University
    The Ohio State University)

  • Baek Kim

    (Emory University)

  • Junran Zhang

    (The Ohio State University
    The Ohio State University
    The Ohio State University)

Abstract

Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i’s) in combination with chemotherapy have shown promising results in preclinical studies but have displayed minimal efficacy with substantial toxicity in clinical trials. To explore combinatorial strategies that can overcome these limitations, we perform an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identify thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a determinant of CHK1i sensitivity. We establish a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR inhibitor auranofin, an approved anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, we show a pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.

Suggested Citation

  • Chandra Bhushan Prasad & Adrian Oo & Yujie Liu & Zhaojun Qiu & Yaogang Zhong & Na Li & Deepika Singh & Xiwen Xin & Young-Jae Cho & Zaibo Li & Xiaoli Zhang & Chunhong Yan & Qingfei Zheng & Qi-En Wang &, 2024. "The thioredoxin system determines CHK1 inhibitor sensitivity via redox-mediated regulation of ribonucleotide reductase activity," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48076-9
    DOI: 10.1038/s41467-024-48076-9
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    References listed on IDEAS

    as
    1. Jonathan Muri & Sebastian Heer & Mai Matsushita & Lea Pohlmeier & Luigi Tortola & Tobias Fuhrer & Marcus Conrad & Nicola Zamboni & Jan Kisielow & Manfred Kopf, 2018. "The thioredoxin-1 system is essential for fueling DNA synthesis during T-cell metabolic reprogramming and proliferation," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    2. Govindi J. Samaranayake & Clara I. Troccoli & Mai Huynh & Rolando D. Z. Lyles & Karen Kage & Andrew Win & Vishalakshi Lakshmanan & Deukwoo Kwon & Yuguang Ban & Steven Xi Chen & Enrique Rodriguez Zarco, 2017. "Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
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