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Nitrate increases cisplatin chemosensitivity of oral squamous cell carcinoma via REDD1/AKT signaling pathway

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Abstract

Although cisplatin is one of the chemotherapeutics most frequently used in oral squamous cell carcinoma (OSCC) treatment, it exerts multiple side effects and poor chemosensitivity. Nitrate reportedly demonstrates several beneficial biological functions, and synthesized nitrates enhance the therapeutic efficacy of chemotherapy. However, the role of inorganic nitrate in cisplatin chemotherapy remains unclear. We therefore investigated the effect of inorganic nitrate exerted on cisplatin sensitivity in OSCC. We found that nitrate did not affect OSCC cell growth and apoptosis in OSCC cells and OSCC xenograft tumor animal studies. Cisplatin induced REDD1 expression and AKT activation in OSCC. However, nitrate could increase cisplatin chemosensitivity, reduce its REDD1 expression, and attenuate AKT signaling activation in OSCC cells. Dysregulation of high levels of REDD1, which could enhance AKT activation, was positively associated with poor prognosis in OSCC patients. Thus, reduced REDD1 expression and retarded AKT activation induced by inorganic nitrate might be a new potential approach to the sensitization of oral cancer to cisplatin treatment in the future.

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Acknowledgements

This work was supported by the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-031), Beijing Hospitals Authority of Hospitals’ Mission Plan (SML20151401, Capital Medical University), Beijing Municipality Government grants (Beijing Scholar Program—PXM2020_014226_000005, PXM2019_014226_000039, PXM2019_014226_000011, PXM2018_014226_000021, PXM2017_014226_000023, PXM2018_193312_000006_0028S643_FCG, PXM2016_014226_000034), and the National Natural Science Foundation of China (91649124)

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  1. Contributed equally to this work

Authors and Affiliations

  1. Beijing Laboratory of Oral Health, Capital Medical University School of Stomatology, Beijing, 100050, China

    Yuanyong Feng, Bin Zhao, Chunyan Song, Liang Hu, Chunmei Zhang, Jinsong Wang & Songlin Wang

  2. Department of Oral and Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266003, China

    Yuanyong Feng & Baoxing Pang

  3. Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China

    Yuanyong Feng & Songlin Wang

  4. Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medical Sciences, Beijing, 100069, China

    Xuedi Cao, Jinsong Wang, Junqi He & Songlin Wang

  5. Research Units of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, 100069, China

    Songlin Wang

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  1. Yuanyong Feng
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  2. Xuedi Cao
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  3. Bin Zhao
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  7. Chunmei Zhang
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  8. Jinsong Wang
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  9. Junqi He
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  10. Songlin Wang
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Correspondence to Junqi He or Songlin Wang.

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Feng, Y., Cao, X., Zhao, B. et al. Nitrate increases cisplatin chemosensitivity of oral squamous cell carcinoma via REDD1/AKT signaling pathway. Sci. China Life Sci. 64, 1814–1828 (2021). https://doi.org/10.1007/s11427-020-1978-4

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