Dysregulation of de novo nucleotide biosynthetic pathway enzymes in cancer and targeting opportunities

Robinson, Alyncia D.; Eich, Marie‐Lisa; Varambally, Sooryanarayana

doi:10.1016/j.canlet.2019.11.013

Cited by 62 publications

(57 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such salvage pathways exist for many key metabolic pathways in the cell, such as nucleotide and sphingolipid biosynthesis. For both of these pathways, in addition to the de novo biosynthesis of essential intermediates like purines/pyrimidines and ceramides, respectively, cells can also obtain these metabolites through extracellular uptake from what is obtained in the diet, as well as degradation of more complex molecules in the cell such as nucleic acids and sphingomyelin [11,15]. Cancer cells can also upregulate processes such as macropinocytosis [16] and autophagy [8], further contributing to their metabolic flexibility in obtaining building blocks.…”

Section: Introductionmentioning

confidence: 99%

“…Antifolates, folate analogs that inhibit de novo nucleotide synthesis enzymes [ 9 , 10 ], were among the very first chemotherapeutics. Since then, many additional therapies that inhibit nucleotide synthesis have been developed and are still used in the clinic to treat several cancers [ 11 ]. Two important examples are the use of 5-fluorouracil, which disrupts thymidine synthesis through the enzyme thymidylate synthase and gemcitabine, which can incorporate into DNA and targets deoxyribonucleotide synthesis through the enzyme ribonucleotide reductase, both of which are required for essential DNA synthesis in rapidly growing cancer cells [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Since then, many additional therapies that inhibit nucleotide synthesis have been developed and are still used in the clinic to treat several cancers [ 11 ]. Two important examples are the use of 5-fluorouracil, which disrupts thymidine synthesis through the enzyme thymidylate synthase and gemcitabine, which can incorporate into DNA and targets deoxyribonucleotide synthesis through the enzyme ribonucleotide reductase, both of which are required for essential DNA synthesis in rapidly growing cancer cells [ 11 ]. In addition to targeting nucleotide synthesis, other biosynthetic pathways have been actively explored and have shown promise in preclinical models, such as PHGDH required for serine biosynthesis and FASN required for fatty acid biosynthesis [ 12 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Endogenous toxic metabolites and implications in cancer therapy

et al. 2020

View full text Add to dashboard Cite

It is well recognized that many metabolic enzymes play essential roles in cancer cells in producing building blocks such as nucleotides, which are required in greater amounts due to their increased proliferation. On the other hand, the significance of enzymes in preventing the accumulation of their substrates is less recognized. Here, we outline the evidence and underlying mechanisms for how many metabolites normally produced in cells are highly toxic, such as metabolites containing reactive groups (e.g., methylglyoxal, 4-hydroxynonenal, and glutaconyl-CoA), or metabolites that act as competitive analogs against other metabolites (e.g., deoxyuridine triphosphate and l-2-hydroxyglutarate). Thus, if a metabolic pathway contains a toxic intermediate, then we may be able to induce accumulation and poison a cancer cell by targeting the downstream enzyme. Furthermore, this poisoning may be cancer cell selective if this pathway is overactive in a cancer cell relative to a nontransformed cell. We describe this concept as illustrated in selenocysteine metabolism and other pathways and discuss future directions in exploiting toxic metabolites to kill cancer cells.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Endogenous toxic metabolites and implications in cancer therapy

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Nucleotides for DNA synthesis may be formed through either de novo synthesis or the nucleoside salvage pathway (53). For the de novo pathway, glucose is converted to phosphoribosyl diphosphate (PRPP) which subsequently leads to the synthesis of purine and pyrimidine precursors, IMP and UMP respectively.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming of Nucleotide Metabolism Mediates Synergy between Epigenetic Therapy and MAP Kinase Inhibition

Shorstova

Shi

Zhao

et al. 2021

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Small Cell Carcinoma of the Ovary, Hypercalcemic Type is a rare but often lethal cancer which is diagnosed at a median age of 24 years. Optimal management of patients is not well defined and current treatment remains challenging, necessitating the discovery of novel therapeutic approaches. The identification of SMARCA4-inactivating mutations invariably characterizing this type of cancer provided insights facilitating diagnostic and therapeutic measures against this disease. We show here that the BET inhibitor OTX015 acts in synergy with the MEK inhibitor cobimetinib to repress the proliferation of SCCOHT in vivo. Notably, this synergy is also observed in some SMARCA4-expressing ovarian adenocarcinoma models intrinsically resistant to BETi. Mass Spectrometry, coupled with knockdown of newly-found targets including thymidylate synthetase, revealed that the repression of a panel of proteins involved in nucleotide synthesis, underlies this synergy both in vitro and in vivo, resulting in reduced pools of nucleotide metabolites and subsequent cell cycle arrest. Overall, our data indicate that dual treatment with BETi and MEKi represents a rational combination therapy against SCCOHT and potentially additional ovarian cancer subtypes.

show abstract

“…FdUMP, the metabolite of 5-FU, combines TYMS to form a ternary complex, thereby inhibiting the normal function of TYMS with the help of 5, 10-MTHF. Therefore, the genetic variants in folic acid metabolic pathway could influence the survival of CRC patients as a deficiency in cell folates leads to point mutations, aberrant DNA methylation, increased frequency of micronuclei and chromosome breakage 22 . In 2014, FH.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants in the Folic acid Metabolic Pathway Genes predict outcomes of metastatic Colorectal Cancer patients receiving first-line Chemotherapy

Jiang

Yuan

et al. 2020

J. Cancer

View full text Add to dashboard Cite

Background: Paclitaxel plays a pivotal role in the chemotherapy of breast cancer, but resistance to this drug is an important obstacle in the treatment. It is reported that microRNA-152-3p (miR-152-3p) is involved in tamoxifen resistance in breast cancer, but whether it is involved in paclitaxel resistance in breast cancer remains unknown. Materials and methods: We examined the expression of miR-152-3p in breast cancer tissues and cells by qRT-PCR. After transfecting paclitaxel-resistant MCF-7/TAX cells with miR-152-3p mimics, we analyzed the function of miR-152-3p in these cells by MTT assay and flow cytometry. We screened the target gene, endothelial PAS domain-containing protein 1 (EPAS1), using bioinformatics analysis and verified it with the dual luciferase reporter gene experiment. The relationship between EPAS1 and miR-152-3p and their roles in paclitaxel resistance of breast cancer were further investigated using RNA interference and transfection techniques. Results: The expression of miR-152-3p in normal breast tissues and cells was markedly higher than that in breast cancer. Overexpression of miR-152-3p decreased the survival rate and increased the apoptosis rate and sensitivity of MCF-7/TAX cells to paclitaxel. We confirmed that EPAS1 is the target of miR-152-3p and is negatively regulated by this miRNA. Moreover, transfection with EPAS1 siRNA enhanced the susceptibility and apoptosis rate of MCF-7/TAX cells to paclitaxel. Co-transfection of miR-152-3p mimics and EPAS1 increased paclitaxel sensitivity and apoptosis induced by the drug. Conclusion: miR-152-3p inhibits the survival of MCF-7/TAX cells and promotes their apoptosis by targeting the expression of EPAS1, thereby, enhancing the sensitivity of these breast cancer cells to paclitaxel.

show abstract

Dysregulation of de novo nucleotide biosynthetic pathway enzymes in cancer and targeting opportunities

Cited by 62 publications

References 68 publications

Endogenous toxic metabolites and implications in cancer therapy

Endogenous toxic metabolites and implications in cancer therapy

Reprogramming of Nucleotide Metabolism Mediates Synergy between Epigenetic Therapy and MAP Kinase Inhibition

Genetic variants in the Folic acid Metabolic Pathway Genes predict outcomes of metastatic Colorectal Cancer patients receiving first-line Chemotherapy

Contact Info

Product

Resources

About