Argininosuccinate synthetase 1 suppression and arginine restriction inhibit cell migration in gastric cancer cell lines

Shan, Yan Shen; Hsu, Hui‐Ping; Lai, Ming Derg; Yen, Meng‐Chi; Chen, Wei Ching; Fang, Jung Hua; Weng, Tzu Yang; Chen, Yi Ling

doi:10.1038/srep09783

Cited by 41 publications

(44 citation statements)

References 44 publications

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“…The upregulated expression of ASS1 has been found to support the proliferation of human colon cancer cells in vitro , as well as the migration and metastatic potential of human gastric cell lines, both in vitro and in mice with tumor xenografts (Bateman et al, 2017; Shan et al, 2015). Yet, the cancer-promoting mechanisms fostered by ASS1 overexpression, and their clinical implications, remain unclear.…”

Section: Metabolic Regulation Of No Synthesis In Cancermentioning

confidence: 99%

Arginine and the metabolic regulation of nitric oxide synthesis in cancer

Keshet

Erez

2018

Disease Models &Amp; Mechanisms

106

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Nitric oxide (NO) is a signaling molecule that plays important roles in diverse biological processes and thus its dysregulation is involved in the pathogenesis of various disorders. In cancer, NO has broad and sometimes dichotomous roles; it is involved in cancer initiation and progression, but also restricts cancer proliferation and invasion, and contributes to the anti-tumor immune response. The importance of NO in a range of cellular processes is exemplified by its tight spatial and dosage control at multiple levels, including via its transcriptional, post-translational and metabolic regulation. In this Review, we focus on the regulation of NO via the synthesis and availability of its precursor, arginine, and discuss the implications of this metabolic regulation for cancer biology and therapy. Despite the established contribution of NO to cancer pathogenesis, the implementation of NO-related cancer therapeutics remains limited, likely due to the challenge of targeting and inducing its protective functions in a cell- and dosage-specific manner. A better understanding of how arginine regulates the production of NO in cancer might thus support the development of anti-cancer drugs that target this key metabolic pathway, and other metabolic pathways involved in NO production.

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Section: Metabolic Regulation Of No Synthesis In Cancermentioning

confidence: 99%

Arginine and the metabolic regulation of nitric oxide synthesis in cancer

Keshet

Erez

2018

Disease Models &Amp; Mechanisms

106

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“…Since aspartate is also an essential precursor for nucleotide synthesis, conversion of aspartate to argininosuccinate by ASS1 can prevent this metabolite to enter nucleotide biosynthesis, possibly resulting in reduced proliferation. ASS1 upregulation has been reported in ovarian, colorectal, gastric and lung cancers, compared to the corresponding normal tissues [21][22][23][24]. While the role of ASS1 in cancer as well as the molecular mechanism mediating ASS1 upregulation remains unclear, it has been described that high ASS1 expression is associated with increased proliferation and tumourigenicity of colorectal cancer [25].…”

Section: Discussionmentioning

confidence: 99%

“…Reduced ASS1 expression in cancer is accompanied by increased aspartate metabolism through the trifunctional protein CAD (Carbamoyl-Phosphate Synthetase 2, Aspartate Transcarbamylase and Dihydroorotase), leading to increased pyrimidine synthesis [27]. Importantly, decreased ASS1 expression or arginine depletion in gastric cancer is described to inhibit cancer cell migration and motility, therefore affecting metastasis formation in vivo [24].…”

Section: Discussionmentioning

confidence: 99%

Integrated metabolomics and transcriptomics analysis of monolayer and neurospheres from glioblastoma cells

Peixoto

Janaki‐Raman

Schlicker

et al. 2020

Preprint

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Background: Altered metabolism is a hallmark of cancer and metabolic reprogramming can regulate several malignant properties to drive tumourigenesis. Metabolic processes contribute to carcinogenesis by modulating proliferation, survival and differentiation. Here, we studied how metabolic pathways are deregulated in cancer stem-like cells, a specific pool of cells that is thought to be responsible for cancer growth and recurrence. Cancer stem-like cells are particularly relevant in glioblastoma (GBM), the most lethal form of primary brain tumours.Methods: We have analysed the transcriptome and metabolome of an established GBM cell line (U87) and a patient-derived GBM stem-like cell line (NCH644) exposed to neurosphere or monolayer culture conditions. By integrating transcriptome and metabolome data, we identified key metabolic pathways and gene signatures that are associated with stem-like and differentiated states in GBM cells.Results: By principal component analysis and hierarchical clustering, we demonstrated that neurospheres and monolayer cells differ substantially in their metabolism and gene regulation. Furthermore, by performing a joint pathway analysis of transcriptome and metabolome data, we found that neurosphere culture conditions induce a similar metabolic rewiring in the two cellular systems and significantly regulate the same metabolic pathways. Finally, arginine biosynthesis was identified as the most significantly regulated pathway in neurospheres from both cell lines, although individual nodes of this pathway were distinctly regulated in the two cellular systems.Conclusions: Neurosphere conditions, as opposed to monolayer conditions, cause a transcriptomic and metabolic rewiring that may be crucial for the regulation of stem-like features. Arginine biosynthesis may be a key metabolic pathway in stemness regulation, by supporting the specific needs of the different cell populations. Different GBM cell lines show distinct regulation of these metabolic pathways, which are crucial to direct metabolites towards nucleotide or arginine synthesis, respectively. Finally, as part of open science data, the data set generated is of great value as a resource for the scientific community.

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“…ASS1 is a rate-limiting enzyme in the citrulline-NO cycle, arginine synthesis, and NO production (16,26,54). Previous studies have shown that ASS1 expression is upregulated in several types of cancer, but the role of ASS1 in cancer as well as the molecular basis mediating ASS1 upregulation remain unclear (18)(19)(20)(21). In KSHV-transformed cells, we found that numerous KSHV-encoded miRNAs were sufficient for upregulating ASS1 expression but to much lesser extents than the whole virus (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…level of STAT3 as a result of complement and Toll-like receptor 4 (TLR4) activation, which promotes the proliferation and survival of KSHV-infected cells (34,35). Moreover, both NO donors and ASS1 have been shown to regulate STAT3 to either promote or inhibit cell proliferation and survival (21,36,37).…”

mentioning

confidence: 99%

Oncogenic Kaposi’s Sarcoma-Associated Herpesvirus Upregulates Argininosuccinate Synthase 1, a Rate-Limiting Enzyme of the Citrulline-Nitric Oxide Cycle, To Activate the STAT3 Pathway and Promote Growth Transformation

Zhu

Cheng

et al. 2019

J Virol

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Cancer cells are required to rewire existing metabolic pathways to support their abnormal proliferation. We have previously shown that, unlike glucose-addicted cancers, Kaposi’s sarcoma-associated herpesvirus (KSHV)-transformed cells depend on glutamine rather than glucose for energy production and amino acid and nucleotide syntheses. High-level consumption of glutamine is tightly regulated and often coupled with the citrulline-nitric oxide (NO) cycle. We have found that KSHV infection accelerates nitrogen efflux by upregulating the expression of argininosuccinate synthase 1 (ASS1), a key enzyme in the citrulline-NO cycle. KSHV utilizes multiple microRNAs to upregulate ASS1 expression. Depletion of either ASS1 or inducible nitric oxide synthase (iNOS) in KSHV-transformed cells suppresses growth proliferation, abolishes colony formation in soft agar, and decreases NO generation. Furthermore, by maintaining intracellular NO levels, ASS1 expression facilitates KSHV-mediated activation of the STAT3 pathway, which is critical for virus-induced transformation. These results illustrate a novel mechanism by which an oncogenic virus hijacks a key metabolic pathway to promote growth transformation and reveal a potential novel therapeutic target for KSHV-induced malignancies. IMPORTANCE We have previously shown that Kaposi’s sarcoma-associated herpesvirus (KSHV)-transformed cells depend on glutamine rather than glucose for energy production and amino acid and nucleotide syntheses. In this study, we have further examined how the KSHV-reprogramed metabolic pathways are regulated and discovered that KSHV hijacks the citrulline-nitric oxide (NO) cycle to promote growth proliferation and transformation. Multiple KSHV-encoded microRNAs upregulate argininosuccinate synthase 1 (ASS1), a key enzyme in the citrulline-NO cycle. ASS1 is required for KSHV-induced proliferation, colony formation in soft agar, and NO generation of KSHV-transformed cells, which also depends on inducible nitric oxide synthase. By maintaining intracellular NO levels, ASS1 mediates KSHV activation of the STAT3 pathway, which is essential for KSHV-induced abnormal cell proliferation and transformation. These results illustrate a novel mechanism by which an oncogenic virus hijacks a key metabolic pathway to promote growth transformation and reveal a potential novel therapeutic target for KSHV-induced malignancies.

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Argininosuccinate synthetase 1 suppression and arginine restriction inhibit cell migration in gastric cancer cell lines

Cited by 41 publications

References 44 publications

Arginine and the metabolic regulation of nitric oxide synthesis in cancer

Arginine and the metabolic regulation of nitric oxide synthesis in cancer

Integrated metabolomics and transcriptomics analysis of monolayer and neurospheres from glioblastoma cells

Oncogenic Kaposi’s Sarcoma-Associated Herpesvirus Upregulates Argininosuccinate Synthase 1, a Rate-Limiting Enzyme of the Citrulline-Nitric Oxide Cycle, To Activate the STAT3 Pathway and Promote Growth Transformation

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