Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers

Kremer, Jeff C.; Prudner, Bethany C.; Lange, Sara Elaine Stubbs; Bean, Gregory R.; Schultze, Matthew; Brashears, Caitlyn B.; Radyk, Megan D.; Redlich, Nathan; Tzeng, Shin Cheng; Kami, Kenjiro; Shelton, Laura M.; Li, Aixiao; Morgan, Zack; Bomalaski, John S.; Tsukamoto, Takashi; McConathy, Jon; Michel, Loren S.; Held, Jason M.; Tine, Brian Andrew Van

doi:10.1016/j.celrep.2016.12.077

Cited by 121 publications

(177 citation statements)

References 52 publications

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“…Tumor cells re-acquire de novo arginine biosynthesis capabilities by ASS1 re-expression [73,77]. It is worth noting that metabolic changes are mostly negligible between ADI-PEG20 treated and untreated cells, providing further evidence for resistance development.…”

Section: Intrinsic and Acquired Resistance Mechanisms Towards Adimentioning

confidence: 89%

“…Finally, Kremer et al identified a treatment-related switch from dependence on aerobic glycolysis (the Warburg effect) to glutamine anaplerosis and mitochondrial oxidative phosphorylation [73]. The Warburg effect is imperative in providing rapidly proliferating cells with pyruvate as an electron acceptor, necessary in the oxidative biosynthesis of aspartate.…”

Section: Stress Responses Upon Adi-based Therapy -Autophagy Senescenmentioning

confidence: 99%

“…The Warburg effect is imperative in providing rapidly proliferating cells with pyruvate as an electron acceptor, necessary in the oxidative biosynthesis of aspartate. Arginine deprivation diverts glucose into the serine biosynthetic pathway, rendering tumor cells more vulnerable to the inhibition of serine biosynthesis and downstream folatedependent enzymes [73].…”

Section: Stress Responses Upon Adi-based Therapy -Autophagy Senescenmentioning

confidence: 99%

“…This can be attributed to suppressed nitric oxide (NO) production [73]. NO is synthesized by NO synthases.…”

Section: Stress Responses Upon Adi-based Therapy -Autophagy Senescenmentioning

confidence: 99%

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Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Riess

Shokraie

Classen

et al. 2018

Cell Physiol Biochem

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Arginine auxotrophy occurs in certain tumor types and is usually caused by the silencing of argininosuccinate synthetase 1 or arginine lyase genes. Such tumors are often associated with an intrinsic chemoresistance and thus a poor prognosis. Arginine auxotrophy however renders these tumors vulnerable to treatment with arginine-degrading enzymes. Among the most frequently applied arginine-degrading agents are bacterial arginine deiminases (ADI). The anti-cancerous effects of ADI derived from different bacteria were extensively studied in numerous preclinical cell culture and xenograft models. Mycoplasma-derived ADI-PEG20 is most commonly used and is currently under clinical investigation as a single agent therapeutic as well as in combination with different antineoplastic compounds. Mechanistically, ADI is capable of reducing metabolic activity in tumor cells, contributing to autophagy, senescence and apoptosis in arginine auxotrophic cells. Although clinical trials are promising, the resistance development upon initial treatment response is an increasing challenge. Furthermore, interference of ADI with the tumor microenvironment is poorly understood. In the present review, we outline recent experimental ADI-based treatment approaches and their translation into the clinic. Furthermore, we summarize new insights into the molecular mechanisms underlying the anti-cancer effects of ADI that might facilitate the refinement of ADI-based combination therapy approaches.

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Section: Intrinsic and Acquired Resistance Mechanisms Towards Adimentioning

confidence: 89%

Section: Stress Responses Upon Adi-based Therapy -Autophagy Senescenmentioning

confidence: 99%

Section: Stress Responses Upon Adi-based Therapy -Autophagy Senescenmentioning

confidence: 99%

“…This can be attributed to suppressed nitric oxide (NO) production [73]. NO is synthesized by NO synthases.…”

Section: Stress Responses Upon Adi-based Therapy -Autophagy Senescenmentioning

confidence: 99%

See 2 more Smart Citations

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Riess

Shokraie

Classen

et al. 2018

Cell Physiol Biochem

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show abstract

“…5,6 One of the many alterations of metabolic pathways that occur upon short-term ADI-PEG20 treatment was the significant redirection of cellular glucose. While cancer cells typically ferment the majority of cellular glucose into lactic acid and oxidize lesser amounts via the TCA cycle, ADI-PEG20 caused a decrease in the flux of glucose-derived carbons into both lactate and TCA cycle intermediates.…”

mentioning

confidence: 99%

Therapeutic arginine starvation in ASS1-deficient cancers inhibits the Warburg effect

Kremer

Tine

2017

Molecular & Cellular Oncology

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Argininosuccinate Synthetase 1 deficiency induces dependence on extracellular arginine for continued cellular growth and survival. Arginine starvation inhibits the Warburg effect and diverts glucose into serine biosynthesis, while simultaneously increasing glutamine metabolism via the tricarboxylic acid cycle. Simultaneous arginine deprivation and inhibition of the subsequent metabolic adaptations induce synthetic lethality.KEYWORDS ADI-PEG20; arginine deiminase; argininosuccinate synthetase 1; ASS1; glutaminase; metabolism; GLS; glucose; glutamine; PHGDH; Warburg Cancer metabolism represents the next wave of cancer therapeutics after immunotherapy. The alterations in cancer cell metabolism that are currently being investigated result from the dramatic metabolic reprogramming that occurs within cancer for the production of biomass. One of the original metabolic hallmarks was the "Warburg Effect," whereby cancer cells preferentially generate energy through glucose fermentation into lactic acid rather than oxidation through the tricarboxylic acid (TCA) cycle and subsequent oxidative phosphorylation. Other common metabolic alterations in cancer include mutations in isocitrate dehydrogenase, overexpression of pyruvate kinase M2 (PKM2), deficiencies in succinate dehydrogenase and fumarate hydratase, and the loss of argininosuccinate synthetase 1 (ASS1) expression. 1 ASS1 is an enzyme involved in clearance of nitrogenous waste via the urea cycle and de novo arginine biosynthesis. Loss of ASS1 expression forces cells to rely on extracellular arginine for continued growth and survival; however, it appears to offer a tumorigenic advantage as loss of ASS1 expression has been shown to be a prognostic biomarker of reduced metastasis-free and overall survival. ASS1-deficient cells undergo autophagy when exposed to the arginine-depleting agent PEGylated arginine deiminase (ADI-PEG20) and undergo cell death upon simultaneous pharmacological or genetic inhibition of autophagy.2,3 Acquired resistance to ADI-PEG20 occurs via a c-Myc-dependent reexpression of ASS1 and renewed cellular arginine biosynthesis capabilities.4,5 Characterization of the cellular consequences of arginine starvation is essential in order to identify and target the metabolic reprogramming that occurs to inhibit the ability of cancer cells to acquire resistance to ADI-PEG20. These findings are being used to develop a biomarker-driven multiagent metabolic therapy for ASS1-deficient cancers.Metabolic characterization of both short-and long-term ADI-PEG20 treatment has shown significant alterations in global metabolism. 5,6 One of the many alterations of metabolic pathways that occur upon short-term ADI-PEG20 treatment was the significant redirection of cellular glucose. While cancer cells typically ferment the majority of cellular glucose into lactic acid and oxidize lesser amounts via the TCA cycle, ADI-PEG20 caused a decrease in the flux of glucose-derived carbons into both lactate and TCA cycle intermediates. The decrease in glucose flux to lactate ...

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PGAM1 regulation of ASS1 contributes to the progression of breast cancer through the cAMP/AMPK/CEBPB pathway

Liu

Wang

et al. 2022

Molecular Oncology

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Phosphoglycerate mutase 1 (PGAM1) is a crucial glycolytic enzyme, and its expression status has been confirmed to be associated with tumor progression and metastasis. However, the precise role and other biological functions of PGAM1 remain unclear. Here, we report that PGAM1 expression is upregulated and related to poor prognosis in patients with breast cancer (BC). Functional experiments showed that knockdown of PGAM1 could suppress the proliferation, invasion, migration, and epithelial–mesenchymal transition of BC cells. Through RNA sequencing, we found that argininosuccinate synthase 1 (ASS1) expression was markedly upregulated in BC cells following PGAM1 knockdown, and it is required to suppress the malignant biological behavior of BC cells. Importantly, we demonstrated that PGAM1 negatively regulates ASS1 expression through the cAMP/AMPK/CEBPB axis. In vivo experiments further validated that PGAM1 promoted tumor growth in BC by altering ASS1 expression. Finally, immunohistochemical analysis showed that downregulated ASS1 levels were associated with PGAM1 expression and poor prognosis in patients with BC. Our study provides new insight into the regulatory mechanism of PGAM1‐mediated BC progression that might shed new light on potential targets and combination therapeutic strategies for BC treatment.

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Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers

Cited by 121 publications

References 52 publications

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Therapeutic arginine starvation in ASS1-deficient cancers inhibits the Warburg effect

PGAM1 regulation of ASS1 contributes to the progression of breast cancer through the cAMP/AMPK/CEBPB pathway

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