The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade.

Autor: Qiu Y; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Stamatatos OT; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Hu Q; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.; Graduate Program in Genetics, Stony Brook University, Stony Brook, NY, USA., Ruiter Swain J; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.; CSHL School of Biological Sciences, Cold Spring Harbor, NY, USA., Russo S; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Sann A; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Costa ASH; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.; Matterworks Inc., Somerville, MA, USA., Violante S; Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Spector DL; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Cross JR; Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Lukey MJ; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. lukey@cshl.edu.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2024 Aug; Vol. 6 (8), pp. 1529-1548. Date of Electronic Publication: 2024 Aug 27.
DOI: 10.1038/s42255-024-01104-w
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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