Asparagine bioavailability regulates the translation of MYC oncogene

Srivastava, Sankalp; Jiang, Jie; Misra, J. C.; Seim, Gretchen; Staschke, Kirk A.; Zhong, Minghua; Zhou, Leonardo; Yu, Liu; Chen, Chong; Davé, Utpal P.; Kapur, Reuben; Batra, Sandeep; Zhang, Chi; Zhou, Jiehao; Fan, Jianqing; Wek, Ron; Zhang, Ji

doi:10.1038/s41388-022-02474-9

Cited by 5 publications

(4 citation statements)

References 53 publications

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“…In addition, to the best of the authors' knowledge, no clinical drugs targeting ASNS have yet been developed. A recent study suggested that inhibition of the production of aspartate can sensitize ASNS high lymphoma to L-asparaginase (48). This conclusion may provide new insights into the treatment of GC with PM and MA.…”

Section: Discussionmentioning

confidence: 78%

Malignant ascites supernatant enhances the proliferation of gastric cancer cells partially via the upregulation of asparagine synthetase

Jiao,

Peng,

Wang

et al. 2023

Oncol Lett

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Malignant ascites (MA) is a common manifestation of advanced gastric cancer (GC) with peritoneal metastasis (PM), which usually indicates a poor prognosis. The present study aimed to explore the effects of MA, a unique microenvironment of PM, on the proliferation of cancer cells and investigate the underlying mechanisms. Ex vivo experiments demonstrated that GC cells treated with MA exhibited enhanced proliferation. RNA sequencing indicated that asparagine synthetase (ASNS) was one of the differentially expressed genes in GC cells following incubation with MAs. Furthermore, the present study suggested that MA induced an upregulation of ASNS expression and the stimulatory effect of MA on cancer cell proliferation was alleviated upon ASNS downregulation. Activating transcription factor 4 (ATF4), a pivotal transcription factor regulating ASNS, was upregulated when cells were treated with MA supernatant. After ATF4 knockdown, the proliferation of MA-treated GC cells and the expression of ASNS decreased. In addition, the decline in the proliferation of the ATF4-downregulated AGS GC cell line was rescued by ASNS upregulation. The findings indicated that MA could promote the proliferation of GC cells via activation of the ATF4-ASNS axis. Hence, it may be a potential target for treating GC with PM and MA.

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Section: Discussionmentioning

confidence: 78%

Malignant ascites supernatant enhances the proliferation of gastric cancer cells partially via the upregulation of asparagine synthetase

Jiao,

Peng,

Wang

et al. 2023

Oncol Lett

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“…As a result, ibrutinib, a BTK inhibitor, suppresses GCN2 activities and synergizes strongly with L-asparaginase in B-ALL, which is currently undergoing clinical trials [ 60 ]. Of interest, a recent work suggests that asparagine starvation can directly inhibit the translation of c-MYC mRNA in leukemia/lymphoma cells [ 61 ]. In a mouse B-cell lymphoma model, they showed that combining L-asparaginase with phenformin, an electron transferring chain (ETC) inhibitor that depletes intracellular aspartate, an indispensable precursor for asparagine, significantly reduced c-MYC expression and lymphoma burden [ 61 ].…”

Section: Asparagine and Its Depletion-based Therapy In All Patientsmentioning

confidence: 99%

“…Of interest, a recent work suggests that asparagine starvation can directly inhibit the translation of c-MYC mRNA in leukemia/lymphoma cells [ 61 ]. In a mouse B-cell lymphoma model, they showed that combining L-asparaginase with phenformin, an electron transferring chain (ETC) inhibitor that depletes intracellular aspartate, an indispensable precursor for asparagine, significantly reduced c-MYC expression and lymphoma burden [ 61 ]. Moreover, the gene encoding the system L amino-acid transporter 1 (LAT1), termed SLC7A5, is overexpressed in ALL and many other proliferating cells [ 62 , 63 ].…”

Section: Asparagine and Its Depletion-based Therapy In All Patientsmentioning

confidence: 99%

Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation

Chen,

Zhang

2024

Cancers

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Cancer cells demand amino acids beyond their usage as “building blocks” for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia.

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“…Depletion of asparagine induces growth inhibition and apoptosis in leukaemia cells [ 35 ], which is partly dependent on huntingtin-associated protein-1 (HAP1) [ 36 ]. Moreover, asparagine depletion reduces MYC protein expression, highlighting the therapeutic potential of suppressing asparagine bioavailability in MYC-driven cancers [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

Metabolism of asparagine in the physiological state and cancer

Yuan,

Yin,

et al. 2024

Cell Commun Signal

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Asparagine, an important amino acid in mammals, is produced in several organs and is widely used for the production of other nutrients such as glucose, proteins, lipids, and nucleotides. Asparagine has also been reported to play a vital role in the development of cancer cells. Although several types of cancer cells can synthesise asparagine alone, their synthesis levels are insufficient to meet their requirements. These cells must rely on the supply of exogenous asparagine, which is why asparagine is considered a semi-essential amino acid. Therefore, nutritional inhibition by targeting asparagine is often considered as an anti-cancer strategy and has shown success in the treatment of leukaemia. However, asparagine limitation alone does not achieve an ideal therapeutic effect because of stress responses that upregulate asparagine synthase (ASNS) to meet the requirements for asparagine in cancer cells. Various cancer cells initiate different reprogramming processes in response to the deficiency of asparagine. Therefore, it is necessary to comprehensively understand the asparagine metabolism in cancers. This review primarily discusses the physiological role of asparagine and the current progress in the field of cancer research.

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Asparagine bioavailability regulates the translation of MYC oncogene

Cited by 5 publications

References 53 publications

Malignant ascites supernatant enhances the proliferation of gastric cancer cells partially via the upregulation of asparagine synthetase

Malignant ascites supernatant enhances the proliferation of gastric cancer cells partially via the upregulation of asparagine synthetase

Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation

Metabolism of asparagine in the physiological state and cancer

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