Loss of asparagine synthetase suppresses the growth of human lung cancer cells by arresting cell cycle at G0/G1 phase

Xu, Yi; Lv, Fanzhen; Zhu, Xunxia; Wu, Yun; Shen, Xiaoyong

doi:10.1038/cgt.2016.28

Cited by 33 publications

(18 citation statements)

References 31 publications

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“…Herein, western blot analysis was performed to evaluate the expression of ASNS in U87MG and U251MG cells and the results indicated that both GBM cells were ASNS-deficient (Figure 1A ). Human highly metastasis lung cancer cell line 95D, which showed drug resistance to asparaginase ( Supplementary Figure 1 ), served as ASNS-positive control [ 46 ] and human acute lymphocytic leukemia cell line Jurkat served as ASNS-negative control [ 47 ]. Therefore, we supposed that U87MG and U251MG cells were sensitive to asparagine deprivation therapy.…”

Section: Resultsmentioning

confidence: 99%

Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo

Chen

Fan

et al. 2017

Oncotarget

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Asparaginase has been reported to be effective in the treatment of various leukemia and several malignant solid cancers. However, the anti-tumor effect of asparaginase is always restricted due to complicated mechanisms. Herein, we investigated the mechanisms of how glioblastoma resisted asparaginase treatment and reported a novel approach to enhance the anti-glioblastoma effect of asparaginase. We found that asparaginase could induce growth inhibition and caspase-dependent apoptosis in U87MG/U251MG glioblastoma cells. Meanwhile, autophagy was activated as indicated by autophagosomes formation and upregulated expression of LC3-II. Importantly, abolishing autophagy using chloroquine (CQ) and LY294002 enhanced the cytotoxicity and apoptosis induced by asparaginase in U87MG/U251MG cells. Further study proved that Akt/mTOR and Erk signaling pathways participated in autophagy induction, while reactive oxygen species (ROS) served as an intracellular regulator for both cytotoxicity and autophagy in asparaginase-treated U87MG/U251MG cells. Moreover, combination treatment with autophagy inhibitor CQ significantly enhanced anti-glioblastoma efficacy of asparaginase in U87MG cell xenograft model.Taken together, our results demonstrated that inhibition of autophagy potentiated the anti-tumor effect of asparagine depletion on glioblastoma, indicating that targeting autophagy and asparagine could be a potential approach for glioblastoma treatment.

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Section: Resultsmentioning

confidence: 99%

Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo

Chen

Fan

et al. 2017

Oncotarget

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“…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). A pharmacological approach was instead adopted by Hettmer et al who demonstrated that an adenylated ASNS inhibitor inhibits the growth of murine and human sarcoma cell lines (58).…”

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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“…ASNS is a member of aminotransferase family ( 26 ). ASNS is related to G1-S phase transition, promoting cell mitosis and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Effect and mechanism of RNAi targeting WWTR1 on biological activity of gastric cancer cells SGC7901

Yang

Zhu

et al. 2017

Mol Med Report

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Abstract. Gastric cancer (GC) is one of the most common malignancies in the world. It is essential to develop novel targets and therapeutic approaches for GC, which requires identification of novel functional molecules. WW-domain containing transcription regulator 1 (WWTR1) may activate many transcriptional factors and exhibit an important role in the development of various tissues in mammals. The results of the present study demonstrated that mRNA and protein levels of WWTR1 are increased in GC tissues and cell lines. The SGC7901 cell line was selected to perform RNA interference (RNAi) targeting WWTR1, and for subsequent study. Compared with control groups (cells without any treatment) and mock groups (cells treated with nonspecific siRNA), cell proliferation of siWWTR1 cells (cells treated with WWTR1 siRNA) was detected using a Cell Counting Kit-8 assay at 12, 24 and 48 h, and decreased in a time-dependent manner. Cell cycle and apoptosis status were determined by flow cytometry, and it was demonstrated that G1/S transition was blocked in the cell cycle and apoptosis promoted in siWWTR1 cells, compared with control and mock cells. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to detect the mRNA and protein levels of cell cycle and apoptosis-associated factors. The expression of Cyclin D1, cancer Myc and B cell lymphoma/leukemia-2 (Bcl-2) decreased and Bcl-2 associated X protein increased significantly in siWWRT1 cells, at the mRNA and protein level, compared with control and mock cells. With the exception of the Hippo pathway, siWWTR1 regulated downstream factors, including mothers against decapentaplegic homolog family member 3 (SMAD3) and inhibitor of DNA binding 1, HLH protein (ID1), HLH protein in the transforming growth factor (TGF)-β pathway. The expression of asparagine synthetase was decreased whereas ID1, SMAD3 (proteins that participate in intracellular TGF-β transduction) and betacellulin increased notably in siWWRT1 cells. In conclusion, WWTR1 promotes cell proliferation and inhibits apoptosis of GC cells by regulating cell cycle/apoptosis-associated factors, and effectors in the TGF-β pathway.

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Loss of asparagine synthetase suppresses the growth of human lung cancer cells by arresting cell cycle at G0/G1 phase

Cited by 33 publications

References 31 publications

Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo

Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo

Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia

Effect and mechanism of RNAi targeting WWTR1 on biological activity of gastric cancer cells SGC7901

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