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

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; Naohiko Kikuchi; Ikuro Sato; Rintaro Saito; Nobuo Yaegashi; Tatsuro Fukuhara; Hidekazu Yamada; Hiroshi Shima; Keiichi I. Nakayama; Atsushi Hirao; Kenta Kawasaki; Yoichi Arai; Shusuke Akamatsu; Sei ichi Tanuma; Toshiro Sato; Takashi Nakagawa; Nobuhiro Tanuma

doi:10.1038/s41467-023-43630-3

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

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, Naohiko Kikuchi, Ikuro Sato, Rintaro Saito, Nobuo Yaegashi, Tatsuro Fukuhara, Hidekazu Yamada, Hiroshi ShimaKeiichi I. Nakayama, Atsushi Hirao, Kenta Kawasaki, Yoichi Arai, Shusuke Akamatsu, Sei ichi Tanuma, Toshiro Sato, Takashi Nakagawa, Nobuhiro Tanuma^*

^*Corresponding author for this work

Molecular and Medical Pharmacology

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English
Article number	8095
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-43630-3
State	Published - 2023/12

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-023-43630-3

Cite this

Nomura, M., Ohuchi, M., Sakamoto, Y., Kudo, K., Yaku, K., Soga, T., Sugiura, Y., Morita, M., Hayashi, K., Miyahara, S., Sato, T., Yamashita, Y., Ito, S., Kikuchi, N., Sato, I., Saito, R., Yaegashi, N., Fukuhara, T., Yamada, H., ... Tanuma, N. (2023). Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma. Nature Communications, 14(1), Article 8095. https://doi.org/10.1038/s41467-023-43630-3

@article{3d16704e27e64138a49509aec38a0538,

title = "Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma",

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.",

author = "Miyuki Nomura and Mai Ohuchi and Yoshimi Sakamoto and Kei Kudo and Keisuke Yaku and Tomoyoshi Soga and Yuki Sugiura and Mami Morita and Kayoko Hayashi and Shuko Miyahara and Taku Sato and Yoji Yamashita and Shigemi Ito and Naohiko Kikuchi and Ikuro Sato and Rintaro Saito and Nobuo Yaegashi and Tatsuro Fukuhara and Hidekazu Yamada and Hiroshi Shima and Nakayama, {Keiichi I.} and Atsushi Hirao and Kenta Kawasaki and Yoichi Arai and Shusuke Akamatsu and Tanuma, {Sei ichi} and Toshiro Sato and Takashi Nakagawa and Nobuhiro Tanuma",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-43630-3",

language = "英語",

volume = "14",

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Nomura, M, Ohuchi, M, Sakamoto, Y, Kudo, K, Yaku, K, Soga, T, Sugiura, Y, Morita, M, Hayashi, K, Miyahara, S, Sato, T, Yamashita, Y, Ito, S, Kikuchi, N, Sato, I, Saito, R, Yaegashi, N, Fukuhara, T, Yamada, H, Shima, H, Nakayama, KI, Hirao, A, Kawasaki, K, Arai, Y, Akamatsu, S, Tanuma, SI, Sato, T, Nakagawa, T & Tanuma, N 2023, 'Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma', Nature Communications, vol. 14, no. 1, 8095. https://doi.org/10.1038/s41467-023-43630-3

TY - JOUR

T1 - Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma

AU - Nomura, Miyuki

AU - Ohuchi, Mai

AU - Sakamoto, Yoshimi

AU - Kudo, Kei

AU - Yaku, Keisuke

AU - Soga, Tomoyoshi

AU - Sugiura, Yuki

AU - Morita, Mami

AU - Hayashi, Kayoko

AU - Miyahara, Shuko

AU - Sato, Taku

AU - Yamashita, Yoji

AU - Ito, Shigemi

AU - Kikuchi, Naohiko

AU - Sato, Ikuro

AU - Saito, Rintaro

AU - Yaegashi, Nobuo

AU - Fukuhara, Tatsuro

AU - Yamada, Hidekazu

AU - Shima, Hiroshi

AU - Nakayama, Keiichi I.

AU - Hirao, Atsushi

AU - Kawasaki, Kenta

AU - Arai, Yoichi

AU - Akamatsu, Shusuke

AU - Tanuma, Sei ichi

AU - Sato, Toshiro

AU - Nakagawa, Takashi

AU - Tanuma, Nobuhiro

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-023-43630-3

DO - 10.1038/s41467-023-43630-3

M3 - 学術論文

C2 - 38092728

AN - SCOPUS:85179643075

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 8095

ER -

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

Abstract

ASJC Scopus subject areas

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