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

Abstract

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.

SLC25A51 impacts drug sensitivity in AML cells by sustaining mitochondrial oxidative flux

“…The results of this study are in line with a growing appreciation that many cancers rely on upregulation of NAD + biosynthetic pathways (30)(31)(32) and mitochondrial activity for growth advantages. In the case of leukemias, there are already several chemotherapeutics with targets related to mitochondrial function, including Venetoclax (33) targeting BCL-2 proteins and multiple electron transport chain Complex I inhibitors, including IACS-010759 (2) and Mubritinib (34).…”

Integrative multi-omics characterization of hepatocellular carcinoma in Hispanic patients

“…When metabolomic profiles of tumors were compared to adjacent non-tumor tissues of STX-Hispanics, we identified 11 significantly enriched pathways, including vitamin B6; nicotinate and nicotinamide; glutamate metabolisms; TCA cycle; and glycolysis and gluconeogenesis. Loss of B vitamins, including B6 (pyridoxine) and B3 (nicotinate or niacin), were previously reported to be associated with hepatocarcinogenesis [77,78]. Metabolites involved in the nicotinate and nicotinamide metabolism process, TCA cycle, and glycolysis and gluconeogenesis were predominantly found at a lower levels in HCC tumors than in adjacent non-tumor tissues, which was associated with significant negative enrichments of these pathways based on the GSEA results from the proteome data of our Hispanic HCC.…”