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Updated: Jun 15, 2025
Glutamine Flux Imaging Using Genetically Encoded Sensors
Published on: July 31, 2014
The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade
Yijian Qiu1, Olivia T Stamatatos1, Qingting Hu1,2
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
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.
Insights
Cancer cells adapt to glutamine starvation by upregulating the serine synthesis pathway (SSP) to produce alpha-ketoglutarate (α-KG). Targeting this adaptive pathway synergizes with glutaminase (GLS) inhibitors to suppress tumor growth.
Area of Science:
- Biochemistry
- Cancer Metabolism
- Molecular Biology
Background:
- Cultured cancer cells often depend on glutamine metabolism via glutaminase (GLS).
- This glutamine dependency can be lost in the tumor microenvironment, limiting the clinical efficacy of GLS inhibitors.
- Understanding cancer cell adaptation to nutrient stress is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the adaptive mechanisms of breast cancer cells to glutamine starvation or GLS inhibition.
- To identify key metabolic pathways and enzymes involved in cancer cell survival under nutrient-limited conditions.
- To explore therapeutic strategies targeting metabolic vulnerabilities in cancer.
Main Methods:
- Utilized cultured breast cancer cells and analyzed metabolic pathway alterations.
- Investigated the role of AMP-activated protein kinase (AMPK) in regulating metabolic pathways.
- Assessed the production of serine and alpha-ketoglutarate (α-KG) by the serine synthesis pathway (SSP).
- Examined the function of phosphoserine aminotransferase 1 (PSAT1) in α-KG production.
- Evaluated the efficacy of combined SSP and GLS inhibition in preclinical models.
Main Results:
- Glutamine-addicted breast cancer cells adapt to glutamine starvation or GLS inhibition by upregulating the SSP via AMPK.
- The primary metabolic output of the upregulated SSP under these conditions is α-KG, not serine.
- Phosphoserine aminotransferase 1 (PSAT1) plays a critical role in sustained α-KG production when glutamate is depleted.
- Cancer cells resistant to glutamine starvation or GLS inhibition exhibit a strong dependence on SSP-derived α-KG.
- Inhibiting the SSP prevents adaptation to glutamine blockade and synergizes with GLS inhibitors to suppress tumor growth.
Conclusions:
- Metabolic redundancy in cancer is context-dependent and influenced by enzyme catalytic properties.
- Breast cancer cells can adapt to glutamine deprivation by rerouting metabolism through the SSP to generate α-KG.
- Targeting the SSP in combination with GLS inhibitors represents a promising therapeutic strategy for overcoming resistance in cancer treatment.
- These findings have significant implications for the design of cancer therapies that target metabolic vulnerabilities.
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