Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis

Rabinovich, Shiran; Adler, Lital N.; Yizhak, Keren; Sarver, Alona; Silberman, Alon; Agron, Shani; Stettner, Noa; Sun, Qin; Brandis, Alexander; Helbling, Daniel; Korman, Stanley H.; Itzkovitz, Shalev; Dimmock, David; Ulitsky, Igor; Nagamani, Sandesh C.S.; Ruppin, Eytan; Erez, Ayelet

doi:10.1038/nature15529

Cited by 307 publications

(291 citation statements)

References 24 publications

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“…Aspartate is a critical metabolite for purine and pyrimidine biosynthesis. Several recent reports have similarly identified aspartate derived from several metabolic pathways as being critical in dividing cells for nucleotide biosynthesis including fatty acid metabolism (23), the urea cycle (24), and TCA cycle-derived citrate (25,26). Consistent with this role for aspartate, the S-phase arrest of KRasdriven cancer cells caused by inhibition of GOT could also be reversed with deoxynucleosides and mimicked with suppression of nucleotide biosynthesis.…”

Section: Discussionsupporting

confidence: 53%

Aspartate Rescues S-phase Arrest Caused by Suppression of Glutamine Utilization in KRas-driven Cancer Cells

Patel

Menon

Bernfeld

et al. 2016

Journal of Biological Chemistry

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During G 1 -phase of the cell cycle, normal cells respond first to growth factors that indicate that it is appropriate to divide and then later in G 1 to the presence of nutrients that indicate sufficient raw material to generate two daughter cells. Dividing cells rely on the "conditionally essential" amino acid glutamine (Q) as an anaplerotic carbon source for TCA cycle intermediates and as a nitrogen source for nucleotide biosynthesis. We previously reported that while non-transformed cells arrest in the latter portion of G 1 upon Q deprivation, mutant KRas-driven cancer cells bypass the G 1 checkpoint, and instead, arrest in S-phase. In this study, we report that the arrest of KRas-driven cancer cells in S-phase upon Q deprivation is due to the lack of deoxynucleotides needed for DNA synthesis. The lack of deoxynucleotides causes replicative stress leading to activation of the ataxia telangiectasia and Rad3-related protein (ATR)-mediated DNA damage pathway, which arrests cells in S-phase. The key metabolite generated from Q utilization was aspartate, which is generated from a transaminase reaction whereby Q-derived glutamate is converted to ␣-ketoglutarate with the concomitant conversion of oxaloacetate to aspartate. Aspartate is a critical metabolite for both purine and pyrimidine nucleotide biosynthesis. This study identifies the molecular basis for the S-phase arrest caused by Q deprivation in KRas-driven cancer cells that arrest in S-phase in response to Q deprivation. Given that arresting cells in S-phase sensitizes cells to apoptotic insult, this study suggests novel therapeutic approaches to KRas-driven cancers.

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Section: Discussionsupporting

confidence: 53%

Aspartate Rescues S-phase Arrest Caused by Suppression of Glutamine Utilization in KRas-driven Cancer Cells

Patel

Menon

Bernfeld

et al. 2016

Journal of Biological Chemistry

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“…As noted above, ASS1 is involved in arginine synthesis, catalyzing the conversion of citrulline and aspartate to the arginine precursor argininosuccinate (Figure 7). Genetic or epigenetic silencing of ASS1 expression provides an advantage to tumor cells by allowing them to preserve cellular aspartate (Rabinovich et al, 2015), a poorly transported nutrient that can be a critical output of the TCA cycle to support de novo nucleotide synthesis and cell proliferation (Birsoy et al, 2015; Sullivan et al, 2015). …”

Section: Altered Metabolic Enzyme Expressionmentioning

confidence: 99%

Targeting Metabolism for Cancer Therapy

Luengo

Gui

Heiden

2017

Cell Chemical Biology

759

624

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Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Chemotherapies targeting metabolism have been effective cancer treatments for decades, and the success of these therapies demonstrates that a therapeutic window exists to target malignant metabolism. New insights into the differential metabolic dependencies of tumors have provided novel therapeutic strategies to exploit altered metabolism, some of which are being evaluated in pre-clinical models or clinical trials. Here, we review our current understanding of cancer metabolism and discuss how this might guide treatments targeting the metabolic requirements of tumor cells.

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“…Recently, it was shown that aspartate is essential for nucleotide synthesis in ASS1-defficient cancer cells. 7 It is well established that many types of tumors are highly dependent of the amino acid glutamine. Furthermore, the expression of many essential amino acid transporters is altered in cancer.…”

Section: Monitoring Amino Acid Deficiencies In Cancermentioning

confidence: 99%