Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function

Jiang, Tingting; Sánchez‐Rivera, Francisco J.; Soto‐Feliciano, Yadira M.; Yang, Qiyuan; Song, Chun‐Qing; Bhuatkar, Arjun; Haynes, Cole M.; Hemann, Michael T.; Xue, Wen

doi:10.1002/hep.31685

Cited by 20 publications

(15 citation statements)

References 51 publications

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“…2A ). Recent studies showed that purine metabolism is linked to liver tumor growth [ 57 ] and glioblastoma radiation resistance [ 58 ]. Our data indicate that purine metabolism is relevant to acquiring drug tolerance to EGFR TKIs in lung cancer.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-21 guide and passenger strand regulation of adenylosuccinate lyase-mediated purine metabolism promotes transition to an EGFR-TKI-tolerant persister state

et al. 2022

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In EGFR-mutant lung cancer, drug-tolerant persister cells (DTPCs) show prolonged survival when receiving EGFR tyrosine kinase inhibitor (TKI) treatments. They are a likely source of drug resistance, but little is known about how these cells tolerate drugs. Ribonucleic acids (RNAs) molecules control cell growth and stress responses. Nucleic acid metabolism provides metabolites, such as purines, supporting RNA synthesis and downstream functions. Recently, noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), have received attention due to their capacity to repress gene expression via inhibitory binding to downstream messenger RNAs (mRNAs). Here, our study links miRNA expression to purine metabolism and drug tolerance. MiR-21-5p (guide strand) is a commonly upregulated miRNA in disease states, including cancer and drug resistance. However, the expression and function of miR-21-3p (passenger strand) are not well understood. We found that upregulation of miR-21-5p and miR-21-3p tune purine metabolism leading to increased drug tolerance. Metabolomics data demonstrated that purine metabolism was the top pathway in the DTPCs compared with the parental cells. The changes in purine metabolites in the DTPCs were partially rescued by targeting miR-21. Analysis of protein levels in the DTPCs showed that reduced expression of adenylosuccinate lyase (ADSL) was reversed after the miR-21 knockdown. ADSL is an essential enzyme in the de novo purine biosynthesis pathway by converting succino-5-aminoimidazole-4-carboxamide riboside (succino-AICAR or SAICAR) to AICAR (or acadesine) as well as adenylosuccinate to adenosine monophosphate (AMP). In the DTPCs, miR-21-5p and miR-21-3p repress ADSL expression. The levels of top decreased metabolite in the DTPCs, AICAR was reversed when miR-21 was blocked. AICAR induced oxidative stress, evidenced by increased reactive oxygen species (ROS) and reduced expression of nuclear factor erythroid-2-related factor 2 (NRF2). Concurrently, miR-21 knockdown induced ROS generation. Therapeutically, a combination of AICAR and osimertinib increased ROS levels and decreased osimertinib-induced NRF2 expression. In a MIR21 knockout mouse model, MIR21 loss-of-function led to increased purine metabolites but reduced ROS scavenging capacity in lung tissues in physiological conditions. Our data has established a link between ncRNAs, purine metabolism, and the redox imbalance pathway. This discovery will increase knowledge of the complexity of the regulatory RNA network and potentially enable novel therapeutic options for drug-resistant patients.

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Section: Resultsmentioning

confidence: 99%

MicroRNA-21 guide and passenger strand regulation of adenylosuccinate lyase-mediated purine metabolism promotes transition to an EGFR-TKI-tolerant persister state

et al. 2022

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“…[ 33 ] Another study suggested that adenylosuccinate lyase (ADSL) is the key enzyme involved in purine metabolism and mitochondrial function during the formation of liver cancer. [ 34 ] Liver cancer cells like many other cancer cells are addicted to glutamine. A chemical library screening of 13 compounds identified glutamine transporter inhibitor targeting alanine‐serine‐cysteine transporter, type‐2 (ASCT2, encoded by gene SLC1A5), V‐9302, showed the greatest synergism with GLS inhibitor, CB‐839, in suppressing HCC cells.…”

Section: Discussionmentioning

confidence: 99%

Genome‐Wide CRISPR/Cas9 Library Screening Revealed Dietary Restriction of Glutamine in Combination with Inhibition of Pyruvate Metabolism as Effective Liver Cancer Treatment

et al. 2022

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Hepatocellular carcinoma (HCC) is the second most lethal cancer worldwide. Glutamine is an essential, extracellular nutrient which supports HCC growth. Dietary glutamine deficiency may be a potential therapeutic approach for HCC. HCC cells overcome metabolic challenges by rewiring their metabolic pathways for rapid adaptations. The efficiency of dietary glutamine deficiency as HCC treatment is examined and the adaptation machinery under glutamine depletion in HCC cells is unraveled. Using genome-wide CRISPR/Cas9 knockout library screening, this study identifies that pyruvate dehydrogenase 𝜶 (PDHA), pyruvate dehydrogenase 𝜷 (PDHB), and pyruvate carboxylase (PC) in pyruvate metabolism are crucial to the adaptation of glutamine depletion in HCC cells. Knockout of either PDHA, PDHB or PC induced metabolic reprogramming of the tricarboxylic acid (TCA) cycle, disrupts mitochondrial function, leading to the suppression of HCC cell proliferation under glutamine depletion. Surprisingly, dietary glutamine restriction improves therapeutic responses of HCC to PDH or PC inhibitor in mouse HCC models. Stable isotope carbon tracing confirms that PDH or PC inhibitors further disrupt the metabolic rewiring of the TCA cycle induced by dietary glutamine depletion in HCC. In summary, the results demonstrate that pyruvate metabolism acts as novel targetable metabolic vulnerabilities for HCC treatment in combination with a glutamine-deficient diet.

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“…MAPRE1 promotes cell cycle progression in hepatocellular carcinoma cells by interacting with CDK2 [31] . Adenylosuccinate lyase (ADSL), a key enzyme involved in the de novo purine synthesis pathway, has been shown to be a potential drug target in HCC [32] . At present, there is no research on AP3B1 and RNP1 in liver cancer, which is worth exploring.…”

Section: Discussionmentioning

confidence: 99%

RNA-sep analysis of circular RNAs and ceRNA networks in human hepatocellular carcinoma

Liu

Dong

Chen

et al. 2022

Preprint

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Objective An increasing number of circular RNAs (circRNAs) have been identified as emerging competing endogenous RNAs (ceRNAs) that play important roles in hepatocellular carcinoma (HCC), but numerous circRNAs remain unexplored. The aim of this study was to explore the mechanism of action of differentially expressed circRNAs and their ceRNA networks in HCC. Methods Second-generation sequencing technology was used to analyse the expression of circRNAs in cancerous and paired paraneoplastic tissues from five patients with HCC. The circRNAs with a P value of less than 0.01, with an original signal value greater than 100 and ranked among the top ten upregulated circRNAs were selected and validated by quantitative reverse transcription polymerase chain reaction (qRT‒PCR) in paired cancer and paraneoplastic tissues from another 34 HCC patients. The downstream miRNAs and mRNAs of the circRNAs were explored through database analysis, and finally, the ceRNA networks and circRNA–miRNA–mRNA axes based on these ten circRNAs were constructed. Results By sequencing, we identified 9658 differentially expressed circRNAs on all chromosomes, of which 3862 were significantly upregulated and 5796 were significantly downregulated. RT-qPCR was performed to validate the top ten upregulated circRNAs, and the results were generally consistent with the sequencing results. After qRT‒PCR validation, five circRNAs (hsa_circ_0079875, hsa_circ0091580, hsa_circ0091581, hsa_circ0004788 and hsa_circ_0059730) were selected for further analysis. First, the downstream miRNAs and mRNAs of these five circRNAs were predicted to construct circRNA-miRNA‒mRNA network diagrams. The 1482 upregulated mRNAs identified in the GEPIA database overlapped with the 278 mRNAs in the ceRNA networks, and 14 overlapping genes were identified. Further bioinformatics analysis revealed four mRNAs (ADSL, AP3B1, MAPRE1, and TRNP1) and five circRNA–miRNA–mRNA axes that were negatively correlated with HCC prognosis. Conclusions Numerous differentially expressed circRNAs exist in HCC, and most can regulate the biological behaviour of HCC through circRNA-miRNA‒mRNA networks. Bioinformatics analysis showed that the ceRNA regulatory axes in HCC have high diagnostic and prognostic value and deserve further exploration. This study aims to provide new research ideas related to HCC pathogenesis and treatment options.

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Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function

Cited by 20 publications

References 51 publications

MicroRNA-21 guide and passenger strand regulation of adenylosuccinate lyase-mediated purine metabolism promotes transition to an EGFR-TKI-tolerant persister state

MicroRNA-21 guide and passenger strand regulation of adenylosuccinate lyase-mediated purine metabolism promotes transition to an EGFR-TKI-tolerant persister state

Genome‐Wide CRISPR/Cas9 Library Screening Revealed Dietary Restriction of Glutamine in Combination with Inhibition of Pyruvate Metabolism as Effective Liver Cancer Treatment

RNA-sep analysis of circular RNAs and ceRNA networks in human hepatocellular carcinoma

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