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Personalized quantitative models of NAD metabolism in hepatocellular carcinoma identify a subgroup with poor prognosis

Cancer cells are known to undergo metabolic adaptation to cater to their enhanced energy demand. Nicotinamide adenine dinucleotide (NAD) is an essential metabolite regulating many cellular processes within the cell. The enzymes required for NAD synthesis, starting from the base precursor - tryptopha...

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Autores principales: Chedere, Adithya, Mishra, Madhulika, Kulkarni, Omkar, Sriraman, Shrisruti, Chandra, Nagasuma
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9565660/
https://www.ncbi.nlm.nih.gov/pubmed/36249025
http://dx.doi.org/10.3389/fonc.2022.954512
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author Chedere, Adithya
Mishra, Madhulika
Kulkarni, Omkar
Sriraman, Shrisruti
Chandra, Nagasuma
author_facet Chedere, Adithya
Mishra, Madhulika
Kulkarni, Omkar
Sriraman, Shrisruti
Chandra, Nagasuma
author_sort Chedere, Adithya
collection PubMed
description Cancer cells are known to undergo metabolic adaptation to cater to their enhanced energy demand. Nicotinamide adenine dinucleotide (NAD) is an essential metabolite regulating many cellular processes within the cell. The enzymes required for NAD synthesis, starting from the base precursor - tryptophan, are expressed in the liver and the kidney, while all other tissues convert NAD from intermediate precursors. The liver, being an active metabolic organ, is a primary contributor to NAD biosynthesis. Inhibition of key enzymes in the NAD biosynthetic pathways is proposed as a strategy for designing anti-cancer drugs. On the other hand, NAD supplementation has also been reported to be beneficial in cancer in some cases. As metabolic adaptation that occurs in cancer cells can lead to perturbations to the pathways, it is important to understand the exact nature of the perturbation in each individual patient. To investigate this, we use a mathematical modelling approach integrated with transcriptomes of patient samples from the TCGA-LIHC cohort. Quantitative profiling of the NAD biosynthesis pathway helps us understand the NAD biosynthetic status and changes in the controlling steps of the pathway. Our results indicate that NAD biosynthesis is heterogeneous among liver cancer patients, and that Nicotinate phosphoribosyl transferase (NAPRT) levels are indicative of the NAD biosynthetic status. Further, we find that reduced NAPRT levels combined with reduced Nicotinamide phosphoribosyl transferase (NAMPT) levels contribute to poor prognosis. Identification of the precise subgroup who may benefit from NAD supplementation in subgroup with low levels of NAPRT and NAMPT could be explored to improve patient outcome.
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spelling pubmed-95656602022-10-15 Personalized quantitative models of NAD metabolism in hepatocellular carcinoma identify a subgroup with poor prognosis Chedere, Adithya Mishra, Madhulika Kulkarni, Omkar Sriraman, Shrisruti Chandra, Nagasuma Front Oncol Oncology Cancer cells are known to undergo metabolic adaptation to cater to their enhanced energy demand. Nicotinamide adenine dinucleotide (NAD) is an essential metabolite regulating many cellular processes within the cell. The enzymes required for NAD synthesis, starting from the base precursor - tryptophan, are expressed in the liver and the kidney, while all other tissues convert NAD from intermediate precursors. The liver, being an active metabolic organ, is a primary contributor to NAD biosynthesis. Inhibition of key enzymes in the NAD biosynthetic pathways is proposed as a strategy for designing anti-cancer drugs. On the other hand, NAD supplementation has also been reported to be beneficial in cancer in some cases. As metabolic adaptation that occurs in cancer cells can lead to perturbations to the pathways, it is important to understand the exact nature of the perturbation in each individual patient. To investigate this, we use a mathematical modelling approach integrated with transcriptomes of patient samples from the TCGA-LIHC cohort. Quantitative profiling of the NAD biosynthesis pathway helps us understand the NAD biosynthetic status and changes in the controlling steps of the pathway. Our results indicate that NAD biosynthesis is heterogeneous among liver cancer patients, and that Nicotinate phosphoribosyl transferase (NAPRT) levels are indicative of the NAD biosynthetic status. Further, we find that reduced NAPRT levels combined with reduced Nicotinamide phosphoribosyl transferase (NAMPT) levels contribute to poor prognosis. Identification of the precise subgroup who may benefit from NAD supplementation in subgroup with low levels of NAPRT and NAMPT could be explored to improve patient outcome. Frontiers Media S.A. 2022-09-30 /pmc/articles/PMC9565660/ /pubmed/36249025 http://dx.doi.org/10.3389/fonc.2022.954512 Text en Copyright © 2022 Chedere, Mishra, Kulkarni, Sriraman and Chandra https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Chedere, Adithya
Mishra, Madhulika
Kulkarni, Omkar
Sriraman, Shrisruti
Chandra, Nagasuma
Personalized quantitative models of NAD metabolism in hepatocellular carcinoma identify a subgroup with poor prognosis
title Personalized quantitative models of NAD metabolism in hepatocellular carcinoma identify a subgroup with poor prognosis
title_full Personalized quantitative models of NAD metabolism in hepatocellular carcinoma identify a subgroup with poor prognosis
title_fullStr Personalized quantitative models of NAD metabolism in hepatocellular carcinoma identify a subgroup with poor prognosis
title_full_unstemmed Personalized quantitative models of NAD metabolism in hepatocellular carcinoma identify a subgroup with poor prognosis
title_short Personalized quantitative models of NAD metabolism in hepatocellular carcinoma identify a subgroup with poor prognosis
title_sort personalized quantitative models of nad metabolism in hepatocellular carcinoma identify a subgroup with poor prognosis
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9565660/
https://www.ncbi.nlm.nih.gov/pubmed/36249025
http://dx.doi.org/10.3389/fonc.2022.954512
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