The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade Journal Article
| Authors: | Qiu, Y.; Stamatatos, O. T.; Hu, Q.; Ruiter Swain, J.; Russo, S.; Sann, A.; Costa, A. S. H.; Violante, S.; Spector, D. L.; Cross, J. R.; Lukey, M. J. |
| Article Title: | The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade |
| Abstract: | 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. © The Author(s), under exclusive licence to Springer Nature Limited 2024. |
| Keywords: | controlled study; unclassified drug; human cell; drug potentiation; nonhuman; mouse; animal tissue; breast cancer; animal experiment; animal model; enzyme activity; genetic transfection; western blotting; cell count; real time polymerase chain reaction; upregulation; catalysis; tumor growth; glutamine; rna extraction; enzyme; starvation; rna isolation; liquid chromatography-mass spectrometry; tumor metabolism; adaptation; human; female; article; rna sequencing; cell viability assay; ic50; phosphoserine aminotransferase 1; ec50; metabolic adaptation; hek293t cell line; hs 578t cell line; mda-mb-231 cell line; bt-474 cell line; mda-mb-468 cell line; glutaminase; hcc1954 cell line; mda-mb-361 cell line; bt-549 cell line; bradford assay; bt-20 cell line; hcc70 cell line |
| Journal Title: | Nature Metabolism |
| Volume: | 6 |
| Issue: | 8 |
| ISSN: | 2522-5812 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-08-01 |
| Start Page: | 1529 |
| End Page: | 1548 |
| Language: | English |
| DOI: | 10.1038/s42255-024-01104-w |
| PROVIDER: | scopus |
| PUBMED: | 39192144 |
| PMCID: | PMC11490312 |
| DOI/URL: | |
| Notes: | Source: Scopus |
