Knockdown of asparagine synthetase by RNAi suppresses cell growth in human melanoma cells and epidermoid carcinoma cells

Li, Hui; Zhou, Fusheng; Du, Wenhui; Dou, Jinfa; Xu, Ye; Gao, Wanwan; Chen, Gang; Zuo, Xianbo; Sun, Liangdan; Zhang, Xuejun; Yang, Sen

doi:10.1002/bab.1383

Cited by 28 publications

(18 citation statements)

References 22 publications

(20 reference statements)

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“…Depletion of functional ASNS in both mouse and human RMS cells reduced the proportion of cells in S phase and impeded synthesis of nascent polypetide chains. Similarly, ASNS silencing in melanoma cells was recently reported to result in cell cycle arrest ( Li et al, 2015 ). The effects of ASNS reduction in sarcoma cells were reversed by exogenous supplementation with asparagine, supporting the notion that rapidly growing sarcoma cells depend on adequate availability of intrinsic or extrinsic asparagine to support tumor growth.…”

Section: Discussionmentioning

confidence: 84%

Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma

Hettmer

Schinzel

Tchessalova

et al. 2015

eLife

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Current therapies for sarcomas are often inadequate. This study sought to identify actionable gene targets by selective targeting of the molecular networks that support sarcoma cell proliferation. Silencing of asparagine synthetase (ASNS), an amidotransferase that converts aspartate into asparagine, produced the strongest inhibitory effect on sarcoma growth in a functional genomic screen of mouse sarcomas generated by oncogenic Kras and disruption of Cdkn2a. ASNS silencing in mouse and human sarcoma cell lines reduced the percentage of S phase cells and impeded new polypeptide synthesis. These effects of ASNS silencing were reversed by exogenous supplementation with asparagine. Also, asparagine depletion via the ASNS inhibitor amino sulfoximine 5 (AS5) or asparaginase inhibited mouse and human sarcoma growth in vitro, and genetic silencing of ASNS in mouse sarcoma cells combined with depletion of plasma asparagine inhibited tumor growth in vivo. Asparagine reliance of sarcoma cells may represent a metabolic vulnerability with potential anti-sarcoma therapeutic value.DOI: http://dx.doi.org/10.7554/eLife.09436.001

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Section: Discussionmentioning

confidence: 84%

Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma

Hettmer

Schinzel

Tchessalova

et al. 2015

eLife

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“…It could increase tumor growth in vivo , inducing expression of genes associated with metastasis and cancer stem cells 20 – 22 . ASNS (asparagine synthetase, ASNS) gene encodes an enzyme that catalyzes glutamine- and ATP-dependent conversion of aspartic acid to asparagine, and its expression is associated with chemotherapy resistance and prognosis in several human cancers 23 – 25 . CXCR1 is a member of the G-protein-coupled receptor family and functions as a receptor for interleukin 8.…”

Section: Discussionmentioning

confidence: 99%

A response prediction model for taxane, cisplatin, and 5-fluorouracil chemotherapy in hypopharyngeal carcinoma

Fang

Huang

Yang

et al. 2018

Sci Rep

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. The five-year survival rate of HNSCC has not improved even with major technological advancements in surgery and chemotherapy. Currently, docetaxel, cisplatin, and 5-fluoruracil (TPF) treatment has been the most popular chemotherapy method for HNSCC; but only a small percentage of HNSCC patients exhibit a good response to TPF treatment. Unfortunately, at present, no reasonably effective prediction model exists to assist clinicians with patient treatment. For this reason, patients have no other alternative but to risk neoadjuvant chemotherapy in order to determine their response to TPF. In this study, we analyzed the gene expression profile in TPF-sensitive and non-sensitive patient samples. We identified a gene expression signature between these two groups. We further chose 10 genes and trained a support vector machine (SVM) model. This model has 88.3% sensitivity and 88.9% specificity to predict the response to TPF treatment in our patients. In addition, four more TPF responsive and four more TPF non-sensitive patient samples were used for further validation. This SVM model has been proven to achieve approximately 75.0% sensitivity and 100% specificity to predict TPF response in new patients. This suggests that our 10-genes SVM prediction model has the potential to assist clinicians to personalize treatment for HNSCC patients.

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“…ASNS mRNA is significantly overexpressed in human gastric cancer samples compared with normal gastric tissue, and its expression inversely correlates with patient survival (50). ASNS knockdown hinders growth of melanoma cells and epidermoid carcinoma cells, inducing cell cycle, down-regulation of CDK4, CDK6, and Cyclin D1, and induction of p21 WAF (56). With a similar approach, Xu et al reported a role for ASNS in the growth and colony formation ability of lung cancer (NSCLC) cells and demonstrated higher ASNS expression in lung cancer tissues than in normal lung tissue (57).…”

Section: High Asns Expression In Cancer: a Pro-tumor Enzyme?mentioning

confidence: 99%

Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia

et al. 2020

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Asparagine Synthetase (ASNS) catalyzes the synthesis of the non-essential amino acid asparagine (Asn) from aspartate (Asp) and glutamine (Gln). ASNS expression is highly regulated at the transcriptional level, being induced by both the Amino Acid Response (AAR) and the Unfolded Protein Response (UPR) pathways. Lack of ASNS protein expression is a hallmark of Acute Lymphoblastic Leukemia (ALL) blasts, which, therefore, are auxotrophic for Asn. This peculiarity is the rationale for the use of bacterial L-Asparaginase (ASNase) for ALL therapy, the first example of anti-cancer treatment targeting a tumor-specific metabolic feature. Other hematological and solid cancers express low levels of ASNS and, therefore, should also be Asn auxotrophs and ASNase sensitive. Conversely, in the last few years, several reports indicate that in some cancer types ASNS is overexpressed, promoting cell proliferation, chemoresistance, and a metastatic behavior. However, enhanced ASNS activity may constitute a metabolic vulnerability in selected cancer models, suggesting a variable and tumor-specific role of the enzyme in cancer. Recent evidence indicates that, beyond its canonical role in protein synthesis, Asn may have additional regulatory functions. These observations prompt a re-appreciation of ASNS activity in the biology of normal and cancer tissues, with particular attention to the fueling of Asn exchange between cancer cells and the tumor microenvironment.

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Knockdown of asparagine synthetase by RNAi suppresses cell growth in human melanoma cells and epidermoid carcinoma cells

Cited by 28 publications

References 22 publications

Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma

Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma

A response prediction model for taxane, cisplatin, and 5-fluorouracil chemotherapy in hypopharyngeal carcinoma

Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia

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