Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer

Lukey, Michael J.; Cluntun, Ahmad A.; Katt, William P.; Lin, Miao-chong J.; Druso, Joseph E.; Ramachandran, Sekar; Erickson, Jon W.; Le, Henry; Wang, Zhihan-Emily; Blank, Bryant S.; Greene, Kai Su; Cerione, Richard A.

doi:10.1016/j.celrep.2019.08.076

Cited by 77 publications

(96 citation statements)

References 38 publications

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“…Previous high-throughput screens revealed that specific lysine residues on GLS are subjected to acylations, a class of PTMs regulated by sirtuin-family enzymes (11,12). To test whether sirtuins influence GLS function in transformed cells, we first used short hairpin RNAs (shRNAs) to knock down each of the mitochondrial family members (SIRT3-5) in MDA-MB-231 breast cancer cells, which express high levels of GLS and are sensitive to GLS-selective inhibitors (30). Western blot analysis showed that depletion of SIRT3 or SIRT4 for 48 h had negligible impact on GLS levels ( Fig.…”

Section: Resultsmentioning

confidence: 99%

SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis

Greene

Lukey

Wang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The mitochondrial enzyme glutaminase (GLS) is frequently up-regulated during tumorigenesis and is being evaluated as a target for cancer therapy. GLS catalyzes the hydrolysis of glutamine to glutamate, which then supplies diverse metabolic pathways with carbon and/or nitrogen. Here, we report that SIRT5, a mitochondrial NAD+-dependent lysine deacylase, plays a key role in stabilizing GLS. In transformed cells, SIRT5 regulates glutamine metabolism by desuccinylating GLS and thereby protecting it from ubiquitin-mediated degradation. Moreover, we show that SIRT5 is up-regulated during cellular transformation and supports proliferation and tumorigenesis. Elevated SIRT5 expression in human breast tumors correlates with poor patient prognosis. These findings reveal a mechanism for increasing GLS expression in cancer cells and establish a role for SIRT5 in metabolic reprogramming and mammary tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis

Greene

Lukey

Wang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Inhibition of GLS, by CB-839 also inhibits growth of TNBC cells but not ER+ breast cancer cells, which rely on GLS2 instead (154). Combining CB-839 with the mTOR inhibitor everolimus, however, does inhibit growth of endocrine-resistant breast cancer xenografts (151,155).…”

Section: Pharmaceutical Targeting Of Metabolism In Breast Cancermentioning

confidence: 99%

HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer

Heer¹,

Jalving²,

Harris³

2020

Journal of Clinical Investigation

218

146

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Hypoxia-inducible factors (HIFs) and the HIF-dependent cancer hallmarks angiogenesis and metabolic rewiring are well-established drivers of breast cancer aggressiveness, therapy resistance, and poor prognosis. Targeting of HIF and its downstream targets in angiogenesis and metabolism has been unsuccessful so far in the breast cancer clinical setting, with major unresolved challenges residing in target selection, development of robust biomarkers for response prediction, and understanding and harnessing escape mechanisms. This Review discusses the pathophysiological role of HIFs, angiogenesis, and metabolism in breast cancer and the challenges of targeting these features in breast cancer patients. Rational therapeutic combinations, especially with immunotherapy and endocrine therapy, seem most promising in the clinical exploitation of the intricate interplay of HIFs, angiogenesis, and metabolism in breast cancer cells and the tumor microenvironment.

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“…Next, glutamine is converted into glutamate by GLSs, amidohydrolase enzymes that catalyze the conversion of glutamine into glutamate, releasing ammonium ions. GLSs have at least three isoforms, GLS1, GLS2, and GAC (a splicing isoform of GLS1), all of which were recently reported to be localized in mitochondria [18][19][20] . Mitochondrial glutamate generated via these catabolic pathways can be exported from mitochondria to the cytosol through the SLC25A18 and SLC25A22 transporters 21 , and cytosolic glutamate then participates in the biosynthesis of glutathione-a tripeptide comprising glutamate, cysteine, and glycineand NEAAs (alanine, proline, aspartate, asparagine, and arginine) and is used as an exchange factor for importing extracellular cystine via SLC7A11.…”

Section: Glutamine Metabolic Pathwaysmentioning

confidence: 99%

Glutamine reliance in cell metabolism

et al. 2020

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As knowledge of cell metabolism has advanced, glutamine has been considered an important amino acid that supplies carbon and nitrogen to fuel biosynthesis. A recent study provided a new perspective on mitochondrial glutamine metabolism, offering mechanistic insights into metabolic adaptation during tumor hypoxia, the emergence of drug resistance, and glutaminolysis-induced metabolic reprogramming and presenting metabolic strategies to target glutamine metabolism in cancer cells. In this review, we introduce the various biosynthetic and bioenergetic roles of glutamine based on the compartmentalization of glutamine metabolism to explain why cells exhibit metabolic reliance on glutamine. Additionally, we examined whether glutamine derivatives contribute to epigenetic regulation associated with tumorigenesis. In addition, in discussing glutamine transporters, we propose a metabolic target for therapeutic intervention in cancer.

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Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer

Cited by 77 publications

References 38 publications

SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis

SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis

HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer

Glutamine reliance in cell metabolism

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