NAD+ salvage pathway in cancer metabolism and therapy

Kennedy, Barry E.; Sharif, Tanveer; Martell, Emma; Dai, Cathleen; Kim, Youra; Lee, Patrick W.K.; Gujar, Shashi

doi:10.1016/j.phrs.2016.10.027

Cited by 105 publications

(110 citation statements)

References 153 publications

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“…Importantly, NAMPT high /PHGDH high cancers appear to be of the poorly tractable, ER-negative, PR-negative, and basal-like subsets. NAMPT inhibitors, currently only marginally successful for cancer therapy (Kennedy et al, 2016), might be more effective if strategically implemented to target PHGDH high tumors.…”

Section: Resultsmentioning

confidence: 99%

The NAD+ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis

et al. 2018

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NAD is a key metabolic redox cofactor that is regenerated from nicotinamide through the NAD salvage pathway. Here, we find that inhibiting the NAD salvage pathway depletes serine biosynthesis from glucose by impeding the NAD-dependent protein, 3-phosphoglycerate dehydrogenase (PHGDH). Importantly, we find that PHGDH breast cancer cell lines are exquisitely sensitive to inhibition of the NAD salvage pathway. Further, we find that PHGDH protein levels and those of the rate-limiting enzyme of NAD salvage, NAMPT, correlate in ER-negative, basal-like breast cancers. Although NAD salvage pathway inhibitors are actively being pursued in cancer treatment, their efficacy has been poor, and our findings suggest that they may be effective for PHGDH-dependent cancers.

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Section: Resultsmentioning

confidence: 99%

The NAD+ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis

et al. 2018

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“…Recall our inhibitor screen and our NAD + metabolism-related sgRNA CRISPR screening analyses indicating that NAD + synthesis in T cells and especially in CD8 + cytotoxic T cells is apparently preferentially based on the NAMPT-regulated salvage pathway. We also discovered from the ovarian cancer patient samples and mouse melanoma tumors that TILs exhibit decreased intracellular NAD + levels while the malignant tumor cells are reported to exhibit much higher NAD + levels compared to normal cells 33,50 . Interestingly, our conditional medium culture experiment also suggested that T cells showed lower NAD + level when cultured with conditional medium, and this could be rescued by addition of exogenous NAD + (Extended Data Fig.…”

Section: Main Textmentioning

confidence: 86%

Potentiating the anti-tumor response of tumor infiltrated T cells by NAD⁺ supplementation

Wang

et al. 2020

Preprint

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Tumor immunotherapies have provided clinical benefits, yet great potential remains for optimizing therapeutic effects. Here, we show that low NAD + levels restrict the function of 20 tumor infiltrating T lymphocytes (TILs). TILs harvested from human ovarian tumor tissues showed decreased NAD + levels compared with T cells from paired peripheral blood samples.The combination of whole-genome CRISPR and large-scale metabolic inhibitor screens implicated the NAD + biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT) is required for T cell activation. Further isotopic labeling and LC-MS studies confirmed that NAD + 25 depletion suppressed mitochondrial energy biosynthesis in T cells. Excitingly, NAD + supplementation significantly enhanced the tumor cell-killing efficacy of CAR-T cells ex vivo, and extended animal survive in both adoptive CAR-T model and immune checkpoint blockade treatment models in vivo. This study demonstrates an over-the-counter nutrient supplement NAD + could robustly boost the efficacy of T cell-based immunotherapy and provides insights 30 into the cellular basis of T cell metabolic reprogramming in treating cancers. One Sentence Summary:NAD + supplementation during cancer immunotherapies significantly enhances T cell activation and tumor killing capacity.Main Text: 35 Cancer immunotherapies including adoptive transfer of naturally-occurring tumor infiltrating lymphocytes (TIL) and genetically-engineered T cells, as well as the use of immune checkpoint inhibitors to boost the function of T cells have emerged as promising approaches to achieve durable clinical responses of otherwise treatment-refractory cancers 1-5 . Although cancer immunotherapies have been successfully utilized in the clinic for subsets of patients, there are 40 several limitations which prevent the broad use of these therapies for entire patient populations 6,7 . Given the function of T cells as key mediators for tumor destruction, their characteristics (e.g., durability, longevity, and killing efficiency, etc.) substantially determine the clinical outcomes of many immunotherapies [8][9][10][11] . Studies have established that successful clearance of tumors mediated by infiltrated T cells can be limited by physical barriers generated by stroma 45 3 cells 12 , immuno-suppressive networks 13 , and nutrient limitations within the microenvironment 14,15 . Thus, efforts to promote the stemness, proliferation and activation capacity of T cells should enable improvements to the efficacy of cancer immunotherapies.Recently, cellular metabolic processes have been reported to shape T cell differentiation and functional activity [16][17][18] . Modulation of metabolic process such as fatty acid catabolism can 50 improve T cell activation and therapeutic function [19][20][21][22][23][24] . It was also reported that there is a strong link between metabolic activity in tumor infiltrated T cells (TIL) and their effector function 25,26 , and stimulation mitochondrial biogenesis via enforced expression of PGC1α resulted in...

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“…In osteosarcoma cells, knockdown of NMNAT2 reduced p53-mediated cell death upon DNA damage [25]. Interestingly, previous study has reported overexpression of NMNAT2 enhanced sensitivity of colorectal cancer cells to specific pro-drug and NAD is an essential coenzyme participating in various energy metabolic pathways, cell signaling regulatory pathways and DNA repair, and a potential therapeutic target for oncotherapy [23]. Higher levels of NAD in cancer cells has been reported [24].…”

Section: Discussionmentioning

confidence: 98%

“…A schematic summary of the current study is illustrated in Figure 6. NAD is an essential coenzyme participating in various energy metabolic pathways, cell signaling regulatory pathways and DNA repair, and a potential therapeutic target for oncotherapy [23]. Higher levels of NAD in cancer cells has been reported [24].…”

Section: Discussionmentioning

confidence: 99%

“…The high glycolytic rate of cancer cells, called "Warburg effect" requires NAD for glycolytic enzymes, and the NAD salvage pathway is important in cancer biology and an intriguing target to prevent cancer growth [23]. Nicotinamide nucleotide adenylyltransferase 2 (NMNAT2) is a cytosolic enzyme that assists in maintaining mitochondrial NAD level, although the association between NAD salvage pathway and mitochondrial NAD level remains unclear [23]. In osteosarcoma cells, knockdown of NMNAT2 reduced p53-mediated cell death upon DNA damage [25].…”

Section: Discussionmentioning

confidence: 99%

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Effects of Epigallocatechin Gallate (EGCG) on Urinary Bladder Urothelial Carcinoma―Next-Generation Sequencing and Bioinformatics Approaches

et al. 2019

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Background and objectives: Bladder urothelial carcinoma is the most common type of genitourinary cancer. Patients with bladder cancer may have limited treatment efficacy related to drug toxicity, resistance or adverse effects, and novel therapeutic strategies to enhance treatment efficacy or increase sensitivity to drugs are of high clinical importance. Epigallocatechin gallate (EGCG) is a polyphenolic compound found in green tea leaves, and a potential anti-cancer agent in various cancer types through modulating and regulating multiple signaling pathways. The current study aimed to explore the role and novel therapeutic targets of EGCG on bladder urothelial carcinoma. Materials and Methods: The BFTC-905 cells, human urinary bladder transitional cell carcinoma (TCC) cell line, were treated with EGCG or water for 24 hours, and the expression profiles of mRNAs and microRNAs were analyzed using next generation sequencing (NGS). The enriched biological functions were determined using different bioinformatics databases. Results: A total of 108 differentially expressed genes in EGCG-treated bladder TCC cells were identified, which were mainly involved in nicotinamide adenine dinucleotide (NAD) biogenesis, inflammatory response and oxidation-reduction metabolism. Moreover, several microRNA-mRNA interactions that potentially participated in the response of bladder TCC to EGCG treatment, including miR-185-3p-ARRB1 (arrestin beta 1), miR-3116-MGAT5B (alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase B), miR-31-5p-TNS1 (tensin 1), miR-642a-5p-TNS1, miR-1226-3p-DLG2 (discs large homolog 2), miR-484-DLG2, and miR-22-3p-PPM1K (protein phosphatase 1K). Conclusions: The current findings provide insights into novel therapeutic targets and underlying mechanisms of action of EGCG treatment in bladder cancer.

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NAD+ salvage pathway in cancer metabolism and therapy

Cited by 105 publications

References 153 publications

The NAD+ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis

The NAD+ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis

Potentiating the anti-tumor response of tumor infiltrated T cells by NAD⁺ supplementation

Effects of Epigallocatechin Gallate (EGCG) on Urinary Bladder Urothelial Carcinoma―Next-Generation Sequencing and Bioinformatics Approaches

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NAD+ salvage pathway in cancer metabolism and therapy

Cited by 105 publications

References 153 publications

The NAD+ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis

The NAD+ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis

Potentiating the anti-tumor response of tumor infiltrated T cells by NAD+ supplementation

Effects of Epigallocatechin Gallate (EGCG) on Urinary Bladder Urothelial Carcinoma―Next-Generation Sequencing and Bioinformatics Approaches

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Potentiating the anti-tumor response of tumor infiltrated T cells by NAD⁺ supplementation