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De-novo NAD(+) synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells

Tryptophan metabolism is essential in diverse kinds of tumors via regulating tumor immunology. However, the direct role of tryptophan metabolism and its signaling pathway in cancer cells remain largely elusive. Here, we establish a mechanistic link from L-type amino acid transporter 1 (LAT1) mediate...

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Autores principales: Liu, Huiying, Xing, Rong, Cheng, Xuefang, Li, Qingran, Liu, Fang, Ye, Hui, Zhao, Min, Wang, Hong, Wang, Guangji, Hao, Haiping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308742/
https://www.ncbi.nlm.nih.gov/pubmed/27566573
http://dx.doi.org/10.18632/oncotarget.11526
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author Liu, Huiying
Xing, Rong
Cheng, Xuefang
Li, Qingran
Liu, Fang
Ye, Hui
Zhao, Min
Wang, Hong
Wang, Guangji
Hao, Haiping
author_facet Liu, Huiying
Xing, Rong
Cheng, Xuefang
Li, Qingran
Liu, Fang
Ye, Hui
Zhao, Min
Wang, Hong
Wang, Guangji
Hao, Haiping
author_sort Liu, Huiying
collection PubMed
description Tryptophan metabolism is essential in diverse kinds of tumors via regulating tumor immunology. However, the direct role of tryptophan metabolism and its signaling pathway in cancer cells remain largely elusive. Here, we establish a mechanistic link from L-type amino acid transporter 1 (LAT1) mediated transport of tryptophan and the subsequent de-novo NAD(+) synthesis to SIRT1-FOXO1 regulated apoptotic signaling in A549 cells in response to NQO1 activation. In response to NQO1 activation, SIRT1 is repressed leading to the increased cellular accumulation of acetylated FOXO1 that transcriptionally activates apoptotic signaling. Decreased uptake of tryptophan due to the downregulation of LAT1 coordinates with PARP-1 hyperactivation to induce rapid depletion of NAD(+) pool. Particularly, the LAT1-NAD(+)-SIRT1 signaling is activated in tumor tissues of patients with non-small cell lung cancer. Because NQO1 activation is characterized with oxidative challenge induced DNA damage, these results suggest that LAT1 and de-novo NAD(+) synthesis in NSCLC cells may play essential roles in sensing excessive oxidative stress.
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spelling pubmed-53087422017-03-09 De-novo NAD(+) synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells Liu, Huiying Xing, Rong Cheng, Xuefang Li, Qingran Liu, Fang Ye, Hui Zhao, Min Wang, Hong Wang, Guangji Hao, Haiping Oncotarget Research Paper Tryptophan metabolism is essential in diverse kinds of tumors via regulating tumor immunology. However, the direct role of tryptophan metabolism and its signaling pathway in cancer cells remain largely elusive. Here, we establish a mechanistic link from L-type amino acid transporter 1 (LAT1) mediated transport of tryptophan and the subsequent de-novo NAD(+) synthesis to SIRT1-FOXO1 regulated apoptotic signaling in A549 cells in response to NQO1 activation. In response to NQO1 activation, SIRT1 is repressed leading to the increased cellular accumulation of acetylated FOXO1 that transcriptionally activates apoptotic signaling. Decreased uptake of tryptophan due to the downregulation of LAT1 coordinates with PARP-1 hyperactivation to induce rapid depletion of NAD(+) pool. Particularly, the LAT1-NAD(+)-SIRT1 signaling is activated in tumor tissues of patients with non-small cell lung cancer. Because NQO1 activation is characterized with oxidative challenge induced DNA damage, these results suggest that LAT1 and de-novo NAD(+) synthesis in NSCLC cells may play essential roles in sensing excessive oxidative stress. Impact Journals LLC 2016-08-23 /pmc/articles/PMC5308742/ /pubmed/27566573 http://dx.doi.org/10.18632/oncotarget.11526 Text en Copyright: © 2016 Liu et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Liu, Huiying
Xing, Rong
Cheng, Xuefang
Li, Qingran
Liu, Fang
Ye, Hui
Zhao, Min
Wang, Hong
Wang, Guangji
Hao, Haiping
De-novo NAD(+) synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells
title De-novo NAD(+) synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells
title_full De-novo NAD(+) synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells
title_fullStr De-novo NAD(+) synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells
title_full_unstemmed De-novo NAD(+) synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells
title_short De-novo NAD(+) synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells
title_sort de-novo nad(+) synthesis regulates sirt1-foxo1 apoptotic pathway in response to nqo1 substrates in lung cancer cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308742/
https://www.ncbi.nlm.nih.gov/pubmed/27566573
http://dx.doi.org/10.18632/oncotarget.11526
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