Anti-apoptotic quinolinate phosphoribosyltransferase ( QPRT ) is a target gene of Wilms' tumor gene 1 (WT1) protein in leukemic cells

Ullmark, Tove; Montano, Giorgia; Järvstråt, Linnea; Nilsson, Helena Jernmark; Håkansson, Erik; Drott, Kristina; Nilsson, Björn; Vidovic, Karina; Gullberg, Urban

doi:10.1016/j.bbrc.2016.11.114

Cited by 21 publications

(24 citation statements)

References 36 publications

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“…In this context, it should be noticed that quinolinate phosphoribosyltransferase (QPRT), which belongs to the phosphoribosyltransferase family and is involved in de novo NAD biosynthesis using quinolinic acid (QA) as a precursor in both prokaryotes and eukaryotes, has not been thoroughly investigated in the context of cancer and inflammation, but there are evidences that also this enzyme might play a role (Hinsch et al, 2009;Sahm et al, 2013;Ullmark et al, 2017;Haslinger et al, 2018).…”

Section: Naprt Is An Important Counterpart To Nampt In Nad Metabolismmentioning

confidence: 99%

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

et al. 2020

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Nicotinamide adenine dinucleotide (NAD) is a cofactor of many enzymatic reactions as well as being a substrate for a number of NAD-consuming enzymes (e.g., PARPS, sirtuins, etc). NAD can be synthesized de novo starting from tryptophan, nicotinamide, nicotinic acid, or nicotinamide riboside from the diet. On the other hand, the nicotinamide that is liberated by NAD-consuming enzymes can be salvaged to reform NAD. In this former instance, nicotinamide phosphoribosyltransferase (NAMPT) is the bottleneck enzyme. In the many cells in which the salvage pathway is predominant, NAMPT, therefore, represents an important controller of intracellular NAD concentrations, and as a consequence of energy metabolism. It is, therefore, not surprising that NAMPT is over expressed by tumoral cells, which take advantage from this to sustain growth rate and tumor progression. This has led to the initiation of numerous medicinal chemistry programs to develop NAMPT inhibitors in the context of oncology. More recently, however, it has been shown that NAMPT inhibitors do not solely target the tumor but also have an effect on the immune system. To add complexity, this enzyme can also be secreted by cells, and in the extracellular space it acts as a cytokine mainly through the activation of Toll like Receptor 4 (TLR4), although it has not been clarified yet if this is the only receptor responsible for its actions. While specific small molecules have been developed only against the intracellular form of NAMPT, growing evidences sustain the possibility to target the extracellular form. In this contribution, the most recent evidences on the medicinal chemistry of NAMPT will be reviewed, together with the key elements that sustain the hypothesis of NAMPT targeting and the drawbacks so far encountered.

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Section: Naprt Is An Important Counterpart To Nampt In Nad Metabolismmentioning

confidence: 99%

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

et al. 2020

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“…In the de novo pathway, tryptophan is first converted to quinolinic acid (QA) through a series of steps; QA is converted to nicotinic acid mononucleotide (NAMN) via quinolinate phosphoribosyltransferase (QPRT) and is then converted to NAD + via nicotinamide nucleotide adenylyltransferase (NMNAT) and NAD synthetase (NADS). In normal cells, QPRT expression follows a tissue-specific distribution; more recent insights have revealed that QPRT expression is altered in some cancer cells (4)(5)(6)(7). The Preiss-Handler pathway converts nicotinic acid (NA) to NAMN through nicotinate phosphoribosyltransferase (NAPRT), an enzyme that is widely expressed in normal tissues but variably expressed in cancer cells (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Heske

2020

Front. Oncol.

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Tumor cells have increased requirements for NAD +. Thus, many cancers exhibit an increased reliance on NAD + production pathways. This dependence may be exploited therapeutically through pharmacological targeting of NAMPT, the rate-limiting enzyme in the NAD + salvage pathway. Despite promising preclinical data using NAMPT inhibitors in cancer models, early NAMPT inhibitors showed limited efficacy in several early phase clinical trials, necessitating the identification of strategies, such as drug combinations, to enhance their efficacy. While the effect of NAMPT inhibitors on impairment of energy metabolism in cancer cells has been well-described, more recent insights have uncovered a number of additional targetable cellular processes that are impacted by inhibition of NAMPT. These include sirtuin function, DNA repair machinery, redox homeostasis, molecular signaling, cellular stemness, and immune processes. This review highlights the recent findings describing the effects of NAMPT inhibitors on the non-metabolic functions of malignant cells, with a focus on how this information can be leveraged clinically. Combining NAMPT inhibitors with other therapies that target NAD +-dependent processes or selecting tumors with specific vulnerabilities that can be co-targeted with NAMPT inhibitors may represent opportunities to exploit the multiple functions of this enzyme for greater therapeutic benefit.

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“…As such, genes identified within this TWAS build upon previously suggested candidate disease mechanisms which may confer MM predisposition [2], including anti-apoptotic effects, roles in DNA double-strand break repair and cell cycle regulation. Furthermore, many of the genes identified have been previously investigated in vitro for their roles in cancer and this adds further support as plausible candidate genes for MM predisposition [24,26,[30][31][32].…”

Section: Discussionmentioning

confidence: 73%

“…This gene has also been implicated in colorectal cancer [30]. A further candidate at this locus, QPRT has been demonstrated to confer resistance to chemotherapy and radiotherapy when studied in glioma and leukaemia [31,32]. As such, genes identified within this TWAS build upon previously suggested candidate disease mechanisms which may confer MM predisposition [2], including anti-apoptotic effects, roles in DNA double-strand break repair and cell cycle regulation.…”

Section: Discussionmentioning

confidence: 85%

Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes

et al. 2019

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Background: While genome-wide association studies (GWAS) of multiple myeloma (MM) have identified variants at 23 regions influencing risk, the genes underlying these associations are largely unknown. To identify candidate causal genes at these regions and search for novel risk regions, we performed a multi-tissue transcriptome-wide association study (TWAS). Results: GWAS data on 7319 MM cases and 234,385 controls was integrated with Genotype-Tissue Expression Project (GTEx) data assayed in 48 tissues (sample sizes, N = 80-491), including lymphocyte cell lines and whole blood, to predict gene expression. We identified 108 genes at 13 independent regions associated with MM risk, all of which were in 1 Mb of known MM GWAS risk variants. Of these, 94 genes, located in eight regions, had not previously been considered as a candidate gene for that locus. Conclusions: Our findings highlight the value of leveraging expression data from multiple tissues to identify candidate genes responsible for GWAS associations which provide insight into MM tumorigenesis. Among the genes identified, a number have plausible roles in MM biology, notably APOBEC3C, APOBEC3H, APOBEC3D, APOBEC3F, APOBEC3G, or have been previously implicated in other malignancies. The genes identified in this TWAS can be explored for follow-up and validation to further understand their role in MM biology.

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Anti-apoptotic quinolinate phosphoribosyltransferase ( QPRT ) is a target gene of Wilms' tumor gene 1 (WT1) protein in leukemic cells

Cited by 21 publications

References 36 publications

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes

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