Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting

Alkan, H. Furkan; Walter, Katharina E.; Luengo, Alba; Madreiter‐Sokolowski, Corina T.; Stryeck, Sarah; Lau, Allison N.; Al-Zoughbi, Wael; Lewis, Caroline A.; Thomas, Craig J.; Höefler, Gerald; Graier, Wolfgang F.; Madl, Tobias; Heiden, Matthew G. Vander; Bogner‐Strauß, Juliane Gertrude

doi:10.1016/j.cmet.2018.07.021

Cited by 139 publications

(176 citation statements)

References 71 publications

Supporting

Mentioning

167

Contrasting

Unclassified

Order By: Relevance

“…Inhibition of the glutaminase disrupts the supply of α‐ketoglutarate to the TCA cycle and therefore interferes with an alternative metabolic pathway for energy production. The availability of the amino acid aspartate has also a strong impact on cell survival, as it influences the dependence of cell on glutamine and could hence offer another approach for a combinatory treatment …”

Section: Combination Studiesmentioning

confidence: 99%

Small‐Molecule Inhibition of Glucose Transporters GLUT‐1–4

Reckzeh

Waldmann

2019

ChemBioChem

View full text Add to dashboard Cite

Glucose addiction is observed in cancer and other diseases that are associated with hyperproliferation. The development of compounds that restrict glucose supply and decrease glycolysis has great potential for the development of new therapeutic approaches. Addressing facilitative glucose transporters (GLUTs), which are often upregulated in glucose‐dependent cells, is therefore of particular interest. This article reviews a selection of potent, isoform‐selective GLUT inhibitors and their biological characterization. Potential therapeutic applications of GLUT inhibitors in oncology and other diseases that are linked to glucose addiction are discussed.

show abstract

Section: Combination Studiesmentioning

confidence: 99%

Small‐Molecule Inhibition of Glucose Transporters GLUT‐1–4

Reckzeh

Waldmann

2019

ChemBioChem

View full text Add to dashboard Cite

show abstract

“…In line with this, we observed that SLC1A3 expression could promote cancer cell metastasis, regardless of asparagine bioavailability (Figs D and EV5E). Even though recent studies mainly focused on the role of SLC1A3 in mediation of aspartate uptake (Alkan et al , ; Garcia‐Bermudez et al , ; Sullivan et al , ; Tajan et al , ), we could not exclude the role of glutamate, which could be converted to aspartate via oxidative or reductive carboxylation. This is supported by our findings that both aspartate and glutamate could rescue ASNase toxicity in SLC1A3 KO or negative cancer cells (Figs H and I).…”

Section: Discussionmentioning

confidence: 94%

“…SLC1A3 is mainly expressed in brain tissues (Fig EV1C), critical for the termination of excitatory neurotransmission (Kanai et al , ). Recent studies have highlighted the importance of SLC1A3‐mediated aspartate uptake for cancer cell proliferation under hypoxia and crosstalk between cancer cells and cancer‐associated fibroblasts in the tumor niche (Alkan et al , ; Garcia‐Bermudez et al , ; Sullivan et al , ; Tajan et al , ; Bertero et al , ). We also observed elevated SLC1A3 RNA levels in several tumor types from the TCGA database [especially kidney renal clear cell carcinoma (KIRC, P = 5.5 × 10 −30 ), kidney renal papillary cell carcinoma (KIRP, P = 2.1 × 10 −10 ), liver hepatocellular carcinoma (LIHC, P = 3.2 × 10 −10 ), and stomach adenocarcinoma (STAD, P = 6.1 × 10 −5 )] (Fig EV1D).…”

Section: Resultsmentioning

confidence: 99%

SLC 1A3 contributes to L‐asparaginase resistance in solid tumors

et al. 2019

View full text Add to dashboard Cite

L‐asparaginase (ASNase) serves as an effective drug for adolescent acute lymphoblastic leukemia. However, many clinical trials indicated severe ASNase toxicity in patients with solid tumors, with resistant mechanisms not well understood. Here, we took a functional genetic approach and identified SLC1A3 as a novel contributor to ASNase resistance in cancer cells. In combination with ASNase, SLC1A3 inhibition caused cell cycle arrest or apoptosis, and myriads of metabolic vulnerabilities in tricarboxylic acid (TCA) cycle, urea cycle, nucleotides biosynthesis, energy production, redox homeostasis, and lipid biosynthesis. SLC1A3 is an aspartate and glutamate transporter, mainly expressed in brain tissues, but high expression levels were also observed in some tumor types. Here, we demonstrate that ASNase stimulates aspartate and glutamate consumptions, and their refilling through SLC1A3 promotes cancer cell proliferation. Lastly, in vivo experiments indicated that SLC1A3 expression promoted tumor development and metastasis while negating the suppressive effects of ASNase by fueling aspartate, glutamate, and glutamine metabolisms despite of asparagine shortage. Altogether, our findings identify a novel role for SLC1A3 in ASNase resistance and suggest that restrictive aspartate and glutamate uptake might improve ASNase efficacy with solid tumors.

show abstract

“…Given that glutamate is a common substrate for both GS and aspartate aminotransferase, an interconnection between aspartate and glutamine metabolism is not surprising. Limiting cytosolic aspartate availability either by depletion of AGC1 (aspartate–glutamate transporter across the mitochondrial membrane) or SLC1A3 (glutamate–aspartate transporter across the plasma membrane) is detrimental for growth under glutamine limitation. Metabolic flux analysis in CHO cells also showed higher flux from aspartate to oxaloacetate in glutamine‐deplete conditions when GS was overexpressed .…”

Section: Discussionmentioning

confidence: 99%

Superfluous glutamine synthetase activity in Chinese Hamster Ovary cells selected under glutamine limitation is growth limiting in glutamine‐replete conditions and can be inhibited by serine

Maralingannavar

Parmar

Panchagnula

et al. 2019

Biotechnology Progress

View full text Add to dashboard Cite

Passaging and expansion of animal cells in lean maintenance medium could result in periods of limitation of some nutrients. Over time, such stresses could possibly result in selection of cells with metabolic changes and contribute to heterogeneity. Here, we investigate whether selection of Chinese Hamster Ovary (CHO) cells under glutamine limitation results in changes in growth under glutamine‐replete conditions. In glutamine‐limiting medium, compared to control cells passaged in glutamine‐rich medium, the selected cells showed higher glutamine synthetase (GS) activity and attained a higher peak viable cell density (PVCD). Surprisingly, in glutamine‐replete conditions, selected cells still showed a higher GS activity but a lower PVCD. We show that in glutamine‐replete medium, PVCD of selected cells was restored on (a) inhibition of GS activity with methionine sulfoximine, (b) supplementation of aspartate—without affecting GS activity, and (c) supplementation of serine, which is reported to inhibit GS in vitro. Consistent with the reported effect of serine, inhibition of GS activity was observed upon serine supplementation along with reduced growth of cells under glutamine‐limiting conditions. The latter observation is important for the design of glutamine‐free culture medium and feed used for GS‐CHO and GS‐NS0. In summary, we show that CHO cells selected under glutamine limitation have superfluous GS activity in glutamine‐replete medium, which negatively affects their PVCD. This may be due to its effect on availability of aspartate which was the limiting nutrient for the growth of selected cells in glutamine‐replete conditions.

show abstract

Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting

Cited by 139 publications

References 71 publications

Small‐Molecule Inhibition of Glucose Transporters GLUT‐1–4

Small‐Molecule Inhibition of Glucose Transporters GLUT‐1–4

SLC 1A3 contributes to L‐asparaginase resistance in solid tumors

Superfluous glutamine synthetase activity in Chinese Hamster Ovary cells selected under glutamine limitation is growth limiting in glutamine‐replete conditions and can be inhibited by serine

Contact Info

Product

Resources

About