Glutamine Stimulates Argininosuccinate Synthetase Gene Expression through Cytosolic O-Glycosylation of Sp1 in Caco-2 Cells

Brasse‐Lagnel, Carole; Fairand, Alain; Lavoinne, Alain; Husson, Annie

doi:10.1074/jbc.m306752200

Cited by 66 publications

(56 citation statements)

References 45 publications

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“…NF-jB, and another transcription factor, Sp1, have both been shown to mediate up-regulation of AS in response to IL-1b and glutamine, respectively, indicating that further validation of these pathways is warranted in ovarian (and other) tumours overexpressing TNF-a and AS. 22,23 The high levels of tumoral AS mRNA and protein expression, co-localising with TNF-a, suggest that inflammatory cytokines are involved in the regulation of this enzyme in vivo. Recent work identified both IL-1b and TNF-a as distinct regulators of AS in the Caco-2 epithelial cell line 22 ; previously, studies employed combinations of inflammatory cytokines to show that AS is inducible maximally (2-to 3-fold) by 24 hr in malignant cell lines.…”

Section: Discussionmentioning

confidence: 99%

Aberrant regulation of argininosuccinate synthetase by TNF‐α in human epithelial ovarian cancer

Szlosarek

Grimshaw

Wilbanks

et al. 2007

Intl Journal of Cancer

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The pro-inflammatory cytokine, tumour necrosis factor-a, TNF-a, is dysregulated in malignant compared with normal ovarian surface epithelium (OSE). Several epidemiological studies have associated inflammation with ovarian tumorigenesis, with TNF-a playing a key role in modulating invasion, angiogenesis and metastasis. Here, we show that TNF-a also induces expression of a rate-limiting enzyme in arginine synthesis, argininosuccinate synthetase (AS), thereby linking inflammation with several argininedependent metabolic pathways, implicated in accelerated carcinogenesis and tumour progression. Having identified AS mRNA induction in TNF-a-treated IGROV-1 ovarian cancer cells, using RNA-arbitrarily primed-PCR, we then observed differential regulation of AS mRNA and protein in malignant, compared with normal, OSE cells. A cDNA cancer profiling array with matched normal ovarian and ovarian tumour samples revealed increased expression of AS mRNA in the latter. Moreover, AS protein colocalised with TNF-a in ovarian cancer cells, with significantly higher levels of AS in malignant compared with normal ovarian tissue. Increased co-expression of AS and TNF-a mRNA was also observed in 2 other epithelial tumours, non-small cell lung and stomach cancer, compared with normal corresponding tissues. In summary, high levels of AS expression, which may be required for several arginine-dependent processes in cancer, including the production of nitric oxide, proline, pyrimidines and polyamines, is regulated by TNF-a and may provide an important molecular pathway linking inflammation and metabolism to ovarian tumorigenesis. ' 2007 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Aberrant regulation of argininosuccinate synthetase by TNF‐α in human epithelial ovarian cancer

Szlosarek

Grimshaw

Wilbanks

et al. 2007

Intl Journal of Cancer

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“…Recently, it has been showed that glutamine stimulates ASS expression in rat hepatocytes and Caco-2 cells through O-glycosylation of Sp1. sites [71]. The expression of ASS also has been showed to be regulated by arginine [72].…”

Section: Why Ass Is Not Expressed In Certain Tumor Types ?mentioning

confidence: 99%

Arginine Deprivation as a Targeted Therapy for Cancer

Feun

You

et al. 2008

CPD

195

188

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Certain cancers may be auxotrophic for a particular amino acid and amino acid deprivation is one method to treat these tumors. Arginine deprivation is a novel approach to target tumors which lack argininosuccinate synthetase (ASS) expression. ASS is a key enzyme which converts citrulline to arginine. Tumors which usually do not express ASS include melanoma, hepatocellular carcinoma, some mesotheliomas and some renal cell cancers. Arginine can be degraded by several enzymes including arginine deiminase (ADI). Although ADI is a microbial enzyme from mycoplasma, it has high affinity to arginine and catalyzes arginine to citrulline and ammonia. Citrulline can be recycled back to arginine in normal cells which express ASS, whereas ASS(−) tumor cells cannot. A pegylated form of ADI (ADI-PEG20) has been formulated and has shown in vitro and in vivo activity against melanoma and hepatocellular carcinoma. ADI-PEG20 induces apoptosis in melanoma cell lines. However, arginine deprivation can also induce ASS expression in certain melanoma cell lines which can lead to in-vitro drug resistance. Phase I and II clinical trials with ADI-PEG20 have been conducted in patients with melanoma and hepatocellular carcinoma and antitumor activity has been demonstrated in both cancers. This article reviews our laboratory and clinical experience as well as others with ADI-PEG20 as an antineoplastic agent. Future direction in utilizing this agent is also discussed.

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“…GLN is a key substrate required for optimal activity of the HBP (2,28). Furthermore, recent evidence reveals that GLN stimulates expression of the argininosuccinate synthetase (ASS) gene via O-glycosylation of Sp1 (2).…”

mentioning

confidence: 99%

“…Furthermore, recent evidence reveals that GLN stimulates expression of the argininosuccinate synthetase (ASS) gene via O-glycosylation of Sp1 (2). Thus, precedent exists for GLN utilizing the HBP to modify gene expression via Sp1.…”

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confidence: 99%

Glutamine enhances heat shock protein 70 expression via increased hexosamine biosynthetic pathway activity

Hamiel

Pinto

Hau

et al. 2009

American Journal of Physiology-Cell Physiology

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Hamiel CR, Pinto S, Hau A, Wischmeyer PE. Glutamine enhances heat shock protein 70 expression via increased hexosamine biosynthetic pathway activity. Am J Physiol Cell Physiol 297: C1509 -C1519, 2009. First published September 23, 2009 doi:10.1152/ajpcell.00240.2009.-Glutamine (GLN) plays a key role in cellular protection following injury via enhancement of heat shock protein 70 (HSP70). The pathway by which GLN enhances HSP70 is unknown. GLN is a key substrate for the hexosamine biosynthetic pathway (HBP), which has been shown to induce HSP70. We sought to explore the role of the HBP in GLN-mediated HSP70 expression. Both chemical inhibitors and small interfering (si)RNA knockdown of key HBP enzymes were used in mouse embryonic fibroblast cells to determine the effects of the HBP on HSP70 expression. The O-glycosylation, nuclear translocation, and transcriptional activation of heat shock factor-1 (HSF-1) and Sp1 were evaluated using immunoprecipitation, Western blotting, and luciferase assays. HSP70 expression levels were evaluated via ELISA and Western blotting. GLN augmented HBP activity before and after heat stress (HS). Chemical inhibition of HBP enzymes reduced GLNmediated HSP70 expression. Specific siRNA targeting of the key HBP enzyme UDP-N-acetylglucosamine (GlcNAc): polypeptide-O-␤-acetylglucosaminyltransferase (OGT) blocked GLN-mediated HSP70 expression and attenuated GLN-mediated cellular protection post-HS. Chemical and siRNA attenuation of the HBP blocked GLN-induced nuclear translocation of Sp1 and HSF-1, which are key to maximal HSP70 expression. Finally, immunoprecipitation revealed HSF-1 was O-glycosylated, and GLN enhanced this effect. These results suggest that metabolism of GLN via the HBP enhances HSP70 expression. This effect appears to be mediated via O-glycosylation, nuclear translocation, and transcriptional activation of Sp1 and HSF-1. This is an important mechanistic description of a pathway that appears responsible for GLNmediated HSP70 expression.heat shock proteins; O-GlcNAc; O-glycosylation; heat shock factor-1; cell protection; cell survival; cell injury HEAT SHOCK PROTEINS (HSPs) are highly conserved proteins involved in the most basic mechanisms of cellular protection. HSP expression following a sublethal insult can induce "stress tolerance" and provide protection from subsequent stress that would otherwise be lethal (8,13,19,20). Previous data indicate that the induction of HSPs (particularly HSP70) can provide significant protection against many forms of injury (8,13,19,20). However, these findings have yet to be applied in a clinical setting because common laboratory inducers of HSPs are not safe for human administration. Our laboratory has shown that glutamine (GLN) can safely enhance HSP expression in in vitro and in vivo settings (9,16,18,23,24). Using genetic knockout models, we have also established that HSP induction is necessary for GLN's beneficial effect following injury (9, 18). Animals and cells that lack the HSP70 gene or the heat shock factor-1 (HSF-1) gene sho...

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Glutamine Stimulates Argininosuccinate Synthetase Gene Expression through Cytosolic O-Glycosylation of Sp1 in Caco-2 Cells

Cited by 66 publications

References 45 publications

Aberrant regulation of argininosuccinate synthetase by TNF‐α in human epithelial ovarian cancer

Aberrant regulation of argininosuccinate synthetase by TNF‐α in human epithelial ovarian cancer

Arginine Deprivation as a Targeted Therapy for Cancer

Glutamine enhances heat shock protein 70 expression via increased hexosamine biosynthetic pathway activity

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