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Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma

Author

Listed:
  • Miyuki Nomura

    (Miyagi Cancer Center Research Institute)

  • Mai Ohuchi

    (Miyagi Cancer Center Research Institute)

  • Yoshimi Sakamoto

    (Miyagi Cancer Center Research Institute)

  • Kei Kudo

    (Miyagi Cancer Center Research Institute
    Tohoku University Graduate School of Medicine
    Tohoku University Graduate School of Medicine)

  • Keisuke Yaku

    (University of Toyama)

  • Tomoyoshi Soga

    (Keio University)

  • Yuki Sugiura

    (Kyoto University Graduate School of Medicine)

  • Mami Morita

    (Miyagi Cancer Center Research Institute)

  • Kayoko Hayashi

    (Miyagi Cancer Center Research Institute)

  • Shuko Miyahara

    (Miyagi Cancer Center Research Institute
    Tohoku University Graduate School of Medicine
    Tohoku University Graduate School of Medicine)

  • Taku Sato

    (Miyagi Cancer Center Research Institute)

  • Yoji Yamashita

    (Miyagi Cancer Center Research Institute)

  • Shigemi Ito

    (Miyagi Cancer Center Research Institute)

  • Naohiko Kikuchi

    (Miyagi Cancer Center Research Institute)

  • Ikuro Sato

    (Miyagi Cancer Center Hospital)

  • Rintaro Saito

    (Keio University)

  • Nobuo Yaegashi

    (Tohoku University Graduate School of Medicine)

  • Tatsuro Fukuhara

    (Miyagi Cancer Center Hospital)

  • Hidekazu Yamada

    (Miyagi Cancer Center Research Institute)

  • Hiroshi Shima

    (Miyagi Cancer Center Research Institute)

  • Keiichi I. Nakayama

    (Kyusyu University
    Tokyo Medical and Dental University)

  • Atsushi Hirao

    (Kanazawa University)

  • Kenta Kawasaki

    (Keio University School of Medicine)

  • Yoichi Arai

    (Miyagi Cancer Center Hospital)

  • Shusuke Akamatsu

    (Kyoto University Graduate School of Medicine
    Nagoya University Graduate School of Medicine)

  • Sei-ichi Tanuma

    (Meikai University Research Institute of Odontology
    University of Human Arts and Sciences)

  • Toshiro Sato

    (Keio University School of Medicine
    Keio University School of Medicine)

  • Takashi Nakagawa

    (University of Toyama)

  • Nobuhiro Tanuma

    (Miyagi Cancer Center Research Institute
    Tohoku University Graduate School of Medicine)

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells is associated with down-regulation of genes relevant to quinolinate phosphoribosyltransferase-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also report that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but nicotinamide riboside kinase 1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations is synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma.

Suggested Citation

  • Miyuki Nomura & Mai Ohuchi & Yoshimi Sakamoto & Kei Kudo & Keisuke Yaku & Tomoyoshi Soga & Yuki Sugiura & Mami Morita & Kayoko Hayashi & Shuko Miyahara & Taku Sato & Yoji Yamashita & Shigemi Ito & Nao, 2023. "Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43630-3
    DOI: 10.1038/s41467-023-43630-3
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    References listed on IDEAS

    as
    1. Mahmoud Ghandi & Franklin W. Huang & Judit Jané-Valbuena & Gregory V. Kryukov & Christopher C. Lo & E. Robert McDonald & Jordi Barretina & Ellen T. Gelfand & Craig M. Bielski & Haoxin Li & Kevin Hu & , 2019. "Next-generation characterization of the Cancer Cell Line Encyclopedia," Nature, Nature, vol. 569(7757), pages 503-508, May.
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