The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
Aug 2024
Aug 2024
Historique:
received:
14
09
2023
accepted:
09
07
2024
medline:
28
8
2024
pubmed:
28
8
2024
entrez:
27
8
2024
Statut:
ppublish
Résumé
Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis by glutaminase (GLS). However, this metabolic addiction can be lost in the tumour microenvironment, rendering GLS inhibitors ineffective in the clinic. Here we show that glutamine-addicted breast cancer cells adapt to chronic glutamine starvation, or GLS inhibition, via AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine, but α-ketoglutarate (α-KG). Mechanistically, we find that phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained α-KG production when glutamate is depleted. Breast cancer cells with resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied α-KG. Accordingly, inhibition of the SSP prevents adaptation to glutamine blockade, resulting in a potent drug synergism that suppresses breast tumour growth. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumour growth in a particular nutrient environment. This, in turn, has practical consequences for therapies targeting cancer metabolism.
Identifiants
pubmed: 39192144
doi: 10.1038/s42255-024-01104-w
pii: 10.1038/s42255-024-01104-w
doi:
Substances chimiques
Glutamine
0RH81L854J
phosphoserine aminotransferase
EC 2.6.1.52
Transaminases
EC 2.6.1.-
Glutaminase
EC 3.5.1.2
Ketoglutaric Acids
0
Serine
452VLY9402
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1529-1548Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : R01GM149957
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : 5P30CA045508
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : 5P01CA013106-Project 3
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
ID : AI140472
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Curthoys, N. P. & Watford, M. Regulation of glutaminase activity and glutamine metabolism. Annu. Rev. Nutr. 15, 133–159 (1995).
pubmed: 8527215
doi: 10.1146/annurev.nu.15.070195.001025
Cluntun, A. A., Lukey, M. J., Cerione, R. A. & Locasale, J. W. Glutamine metabolism in cancer: understanding the heterogeneity. Trends Cancer 3, 169–180 (2017).
pubmed: 28393116
pmcid: 5383348
doi: 10.1016/j.trecan.2017.01.005
Altman, B. J., Stine, Z. E. & Dang, C. V. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat. Rev. Cancer 16, 619–634 (2016).
pubmed: 27492215
pmcid: 5484415
doi: 10.1038/nrc.2016.71
Wang et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18, 207–219 (2010).
pubmed: 20832749
pmcid: 3078749
doi: 10.1016/j.ccr.2010.08.009
Gross, M. I. et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol. Cancer Ther. 13, 890–901 (2014).
pubmed: 24523301
doi: 10.1158/1535-7163.MCT-13-0870
Yang, W. H., Qiu, Y., Stamatatos, O., Janowitz, T. & Lukey, M. J. Enhancing the efficacy of glutamine metabolism inhibitors in cancer therapy. Trends Cancer 7, 790–804 (2021).
pubmed: 34020912
pmcid: 9064286
doi: 10.1016/j.trecan.2021.04.003
DeBerardinis, R. J. & Cheng, T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29, 313–324 (2010).
pubmed: 19881548
doi: 10.1038/onc.2009.358
Cheng, T. et al. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc. Natl Acad. Sci. USA 108, 8674–8679 (2011).
pubmed: 21555572
pmcid: 3102381
doi: 10.1073/pnas.1016627108
Dos Reis, L. M. et al. Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells. J. Biol. Chem. 294, 9342–9357 (2019).
pubmed: 31040181
pmcid: 6579458
doi: 10.1074/jbc.RA119.008180
Daemen, A. et al. Pan-cancer metabolic signature predicts co-dependency on glutaminase and de novo glutathione synthesis linked to a high-mesenchymal cell state. Cell Metab. 28, 383–399 (2018).
pubmed: 30043751
doi: 10.1016/j.cmet.2018.06.003
Timmerman, L. et al. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell 24, 450–465 (2013).
pubmed: 24094812
pmcid: 3931310
doi: 10.1016/j.ccr.2013.08.020
Muir, A. et al. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. Elife 6, e27713 (2017).
pubmed: 28826492
pmcid: 5589418
doi: 10.7554/eLife.27713
Shin, C. S. et al. The glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility. Nat. Commun. 8, 15074 (2017).
pubmed: 28429737
pmcid: 5413954
doi: 10.1038/ncomms15074
Lukey, M. J., Greene, K. S., Erickson, J. W., Wilson, K. F. & Cerione, R. A. The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy. Nat. Commun. 7, 11321 (2016).
pubmed: 27089238
pmcid: 4837472
doi: 10.1038/ncomms11321
Pan, M. et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat. Cell Biol. 18, 1090–1101 (2016).
pubmed: 27617932
pmcid: 5536113
doi: 10.1038/ncb3410
Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015).
pubmed: 25644265
pmcid: 4316379
doi: 10.1158/0008-5472.CAN-14-2211
Edwards, D. N. et al. Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer. J. Clin. Invest. 131, e140100 (2021).
pubmed: 33320840
pmcid: 7880417
doi: 10.1172/JCI140100
Pavlova, N. N. et al. As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab. 27, 428–438 (2018).
pubmed: 29337136
pmcid: 5803449
doi: 10.1016/j.cmet.2017.12.006
Pacold, M. E. et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat. Chem. Biol. 12, 452–458 (2016).
pubmed: 27110680
pmcid: 4871733
doi: 10.1038/nchembio.2070
Weinstabl, H. et al. Intracellular trapping of the selective phosphoglycerate dehydrogenase (PHGDH) inhibitor BI-4924 disrupts serine biosynthesis. J. Med. Chem. 62, 7976–7997 (2019).
pubmed: 31365252
doi: 10.1021/acs.jmedchem.9b00718
Possemato, R. et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346–350 (2011).
pubmed: 21760589
pmcid: 3353325
doi: 10.1038/nature10350
Fell, D. A. & Snell, K. Control analysis of mammalian serine biosynthesis. Feedback inhibition on the final step. Biochem. J. 256, 97–101 (1988).
pubmed: 2851987
pmcid: 1135373
doi: 10.1042/bj2560097
Koper, K., Han, S. W., Pastor, D. C., Yoshikuni, Y. & Maeda, H. A. Evolutionary origin and functional diversification of aminotransferases. J. Biol. Chem. 298, 102122 (2022).
pubmed: 35697072
pmcid: 9309667
doi: 10.1016/j.jbc.2022.102122
Ouzounis, C. & Sander, C. Homology of the NifS family of proteins to a new class of pyridoxal phosphate-dependent enzymes. FEBS Lett. 322, 159–164 (1993).
pubmed: 8482384
doi: 10.1016/0014-5793(93)81559-I
Chen, W. W., Freinkman, E., Wang, T., Birsoy, K. & Sabatini, D. M. Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism. Cell 166, 1324–1337 (2016).
pubmed: 27565352
pmcid: 5030821
doi: 10.1016/j.cell.2016.07.040
Bailey, J., Bell, E. T. & Bell, J. E. Regulation of bovine glutamate dehydrogenase. The effects of pH and ADP. J. Biol. Chem. 257, 5579–5583 (1982).
pubmed: 7068608
doi: 10.1016/S0021-9258(19)83816-4
Glinghammar, B. et al. Detection of the mitochondrial and catalytically active alanine aminotransferase in human tissues and plasma. Int. J. Mol. Med. 23, 621–631 (2009).
pubmed: 19360321
doi: 10.3892/ijmm_00000173
Huynh, Q. K., Sakakibara, R., Watanabe, T. & Wada, H. Glutamic oxaloacetic transaminase isozymes from rat liver. J. Biochem. 88, 231–239 (1980).
pubmed: 7410335
Davoodi, J. et al. Overexpression and characterization of the human mitochondrial and cytosolic branched-chain aminotransferases. J. Biol. Chem. 273, 4982–4989 (1998).
pubmed: 9478945
doi: 10.1074/jbc.273.9.4982
Matsuzawa, T. Characteristics of the inhibition of ornithine-δ-aminotransferase by branched-chain amino acids. J. Biochem. 75, 601–609 (1974).
pubmed: 4834653
doi: 10.1093/oxfordjournals.jbchem.a130428
Chou, T. C. Drug combination studies and their synergy quantification using the Chou–Talalay method. Cancer Res. 70, 440–446 (2010).
pubmed: 20068163
doi: 10.1158/0008-5472.CAN-09-1947
Fazzari, J. & Singh, G. Effect of glutaminase inhibition on cancer-induced bone pain. Breast Cancer Targets Ther. 11, 273–282 (2019).
doi: 10.2147/BCTT.S215655
Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374–1395 (2016).
pubmed: 27629041
pmcid: 5048378
doi: 10.15252/embr.201642195
Garcia, D. & Shaw, R. J. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol. Cell 66, 789–800 (2017).
pubmed: 28622524
pmcid: 5553560
doi: 10.1016/j.molcel.2017.05.032
Selvarajah, B. et al. mTORC1 amplifies the ATF4-dependent de novo serine-glycine pathway to supply glycine during TGF-β1-induced collagen biosynthesis. Sci. Signal 12, 3048 (2019).
doi: 10.1126/scisignal.aav3048
Myers, R. W. et al. Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy. Science 357, 507–511 (2017).
pubmed: 28705990
doi: 10.1126/science.aah5582
Yun, H. J. et al. AMPK-HIF-1α signaling enhances glucose-derived de novo serine biosynthesis to promote glioblastoma growth. J. Exp. Clin. Cancer Res. 42, 340 (2023).
pubmed: 38098117
pmcid: 10722853
doi: 10.1186/s13046-023-02927-3
DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non–small cell lung cancer. Nat. Genet. 47, 1475–1481 (2015).
pubmed: 26482881
pmcid: 4721512
doi: 10.1038/ng.3421
Joo, M. S. et al. AMPK facilitates nuclear accumulation of Nrf2 by phosphorylating at serine 550. Mol. Cell. Biol. 36, 1931–1942 (2016).
pubmed: 27161318
pmcid: 4936058
doi: 10.1128/MCB.00118-16
Lukey, M. J., Katt, W. P. & Cerione, R. A. Targeting amino acid metabolism for cancer therapy. Drug Discov. Today 22, 796–804 (2017).
pubmed: 27988359
doi: 10.1016/j.drudis.2016.12.003
Baixauli, F. et al. An LKB1–mitochondria axis controls TH17 effector function. Nature 610, 555–561 (2022).
pubmed: 36171294
pmcid: 9844518
doi: 10.1038/s41586-022-05264-1
Kottakis, F. et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 539, 390–395 (2016).
pubmed: 27799657
pmcid: 5988435
doi: 10.1038/nature20132
Galan-Cobo, A. et al. LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence in KRAS-mutant lung adenocarcinoma. Cancer Res. 79, 3251–3267 (2019).
pubmed: 31040157
pmcid: 6606351
doi: 10.1158/0008-5472.CAN-18-3527
Ho, C. L., Noji, M., Saito, M., Yamazaki, M. & Saito, K. Molecular characterization of plastidic phosphoserine aminotransferase in serine biosynthesis from Arabidopsis. Plant J. 16, 443–452 (1998).
pubmed: 9881164
doi: 10.1046/j.1365-313x.1998.00313.x
Singh, R. K., Kumar, D. & Gourinath, S. Phosphoserine aminotransferase has conserved active site from microbes to higher eukaryotes with minor deviations. Protein Pept. Lett. 28, 996–1008 (2021).
pubmed: 33588715
doi: 10.2174/0929866528666210215140231
Lund, K., Merrill, D. K. & Guynn, R. W. The reactions of the phosphorylated pathway of L-serine biosynthesis: thermodynamic relationships in rabbit liver in vivo. Arch. Biochem. Biophys. 237, 186–196 (1985).
pubmed: 2982327
doi: 10.1016/0003-9861(85)90268-1
Marchesani, F. et al. A novel assay for phosphoserine phosphatase exploiting serine acetyltransferase as the coupling enzyme. Life 11, 485 (2021).
pubmed: 34073563
pmcid: 8229081
doi: 10.3390/life11060485
Luo, Z., Eichinger, K. M., Zhang, A. & Li, S. Targeting cancer metabolic pathways for improving chemotherapy and immunotherapy. Cancer Lett. 575, 216396 (2023).
pubmed: 37739209
doi: 10.1016/j.canlet.2023.216396
Zecchini, V. & Frezza, C. Metabolic synthetic lethality in cancer therapy. Biochim. Biophys. Acta Bioenerg. 1858, 723–731 (2017).
pubmed: 27956047
doi: 10.1016/j.bbabio.2016.12.003
Christen, S. et al. Breast cancer-derived lung metastases show increased pyruvate carboxylase-dependent anaplerosis. Cell Rep. 17, 837–848 (2016).
pubmed: 27732858
doi: 10.1016/j.celrep.2016.09.042
Abla, H., Sollazzo, M., Gasparre, G., Iommarini, L. & Porcelli, A. M. The multifaceted contribution of α-ketoglutarate to tumor progression: an opportunity to exploit? Semin. Cell Dev. Biol. 98, 26–33 (2020).
pubmed: 31175937
doi: 10.1016/j.semcdb.2019.05.031
Hwang, I. Y. et al. Psat1-dependent fluctuations in α-ketoglutarate affect the timing of ESC differentiation. Cell Metab. 24, 494–501 (2016).
pubmed: 27476977
doi: 10.1016/j.cmet.2016.06.014
Kaushik, A. K. et al. In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma. Sci. Adv. 8, eabp8293 (2022).
pubmed: 36525494
pmcid: 9757752
doi: 10.1126/sciadv.abp8293
Locasale, J. W. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat. Genet. 43, 869–874 (2011).
pubmed: 21804546
pmcid: 3677549
doi: 10.1038/ng.890
Sullivan, M. R. et al. Increased serine synthesis provides an advantage for tumors arising in tissues where serine levels are limiting. Cell Metab. 29, 1410–1421 (2019).
pubmed: 30905671
pmcid: 6551255
doi: 10.1016/j.cmet.2019.02.015
Mattaini, K. R., Sullivan, M. R. & Vander Heiden, M. G. The importance of serine metabolism in cancer. J. Cell Biol. 214, 249–257 (2016).
pubmed: 27458133
pmcid: 4970329
doi: 10.1083/jcb.201604085
Wang, Z. & Zhang, J. Abundant indispensable redundancies in cellular metabolic networks. Genome Biol. Evol. 1, 23–33 (2009).
pubmed: 20333174
pmcid: 2817398
doi: 10.1093/gbe/evp002
Sambamoorthy, G. & Raman, K. Understanding the evolution of functional redundancy in metabolic networks. Bioinformatics 34, i981–i987 (2018).
pubmed: 30423058
pmcid: 6129275
doi: 10.1093/bioinformatics/bty604
Marx, C. J., Van Dien, S. J. & Lidstrom, M. E. Flux analysis uncovers key role of functional redundancy in formaldehyde metabolism. PLoS Biol. 3, e16 (2005).
pubmed: 15660163
pmcid: 539335
doi: 10.1371/journal.pbio.0030016
Bhatia, S. et al. Patient-derived triple-negative breast cancer organoids provide robust model systems that recapitulate tumor intrinsic characteristics. Cancer Res. 82, 1174–1192 (2022).
pubmed: 35180770
pmcid: 9135475
doi: 10.1158/0008-5472.CAN-21-2807
Chou, T.-C. The mass-action law based algorithm for cost-effective approach for cancer drug discovery and development. Am. J. Cancer Res 1, 925–954 (2011).
pubmed: 22016837
pmcid: 3196289
Chou, T.-C. & Martin, N. CompuSyn for Drug Combinations: PC Software and User’s Guide: A Computer Program for Quantitation of Synergism and Antagonism in Drug Combinations, and the Determination of IC
Sanjana, N. E., Shalem, O. & Zhang, F. Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods 11, 783–784 (2014).
pubmed: 25075903
pmcid: 4486245
doi: 10.1038/nmeth.3047
Peracchi, A. & Polverini, E. Using steady-state kinetics to quantitate substrate selectivity and specificity: a case study with two human transaminases. Molecules 27, 1398 (2022).
pubmed: 35209187
pmcid: 8875635
doi: 10.3390/molecules27041398
Basurko, M.-J., Marche, M., Darriet, M. & Cassaigne, A. Phosphoserine aminotransferase, the second step-catalyzing enzyme for serine biosynthesis. IUBMB Life 48, 525–529 (1999).
pubmed: 10637769
Lineweaver, H. & Burk, D. The determination of enzyme dissociation constants. J. Am. Chem. Soc. 56, 658–666 (1934).
doi: 10.1021/ja01318a036
MacKay, G. M., Zheng, L., Van Den Broek, N. J. F. & Gottlieb, E. Analysis of cell metabolism using LC–MS and isotope tracers. Methods Enzymol. 561, 171–196 (2015).
pubmed: 26358905
doi: 10.1016/bs.mie.2015.05.016
Su, X., Lu, W. & Rabinowitz, J. D. Metabolite spectral accuracy on orbitraps. Anal. Chem. 89, 5940–5948 (2017).
pubmed: 28471646
pmcid: 5748891
doi: 10.1021/acs.analchem.7b00396