Amino Acid Transport Mechanisms in Cancer Metabolism

Cancer cells reprogramme their metabolism to sustain rapid proliferation and survival under stress. Central to this reprogramming is the upregulation of specialised membrane transporters that mediate the uptake and exchange of amino acids. Sodium-dependent transporters such as ASCT2 (SLC1A5) and the SNAT family (SLC38A1/2) import glutamine and other neutral amino acids, while sodium-independent system L transporters (LAT1, LAT2) exchange intracellular substrates for essential amino acids such as leucine. These transporters often require heteromeric assembly with heavy-chain proteins like CD98hc for proper trafficking and function. Enhanced uptake drives the mechanistic target of rapamycin complex 1 (mTORC1) signalling axis, promoting anabolic growth, redox balance and resistance to nutrient stress. Redundancy among transporter isoforms ensures robustness of amino acid supply, and adaptive compensation—such as upregulation of SNAT1/2 upon ASCT2 loss—underscores the complexity of targeting these systems. Therapeutically, inhibitors of transporter function and antibody–drug conjugates targeting surface subunits have shown promise in preclinical cancer models, highlighting a globally significant avenue for novel anticancer strategies.

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Amino Acid Transport Mechanisms in Cancer Metabolism publication trend

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Technical terms

Amino acid transporter: Membrane proteins that mediate cellular uptake and exchange of amino acids via co-transport, antiport or facilitated diffusion.

CD98hc (SLC3A2): Heavy-chain glycoprotein that heterodimerises with light-chain transporters (e.g., LAT1) to enable plasma membrane localisation of the functional complex.

LAT1 (SLC7A5): Sodium-independent exchanger importing essential amino acids in exchange for intracellular substrates; frequently overexpressed in tumours.

ASCT2 (SLC1A5): Sodium-dependent antiporter that primarily mediates glutamine uptake and exchange of neutral amino acids, supporting biosynthesis and energy production.

mTORC1: Mechanistic target of rapamycin complex 1, a central nutrient sensor that regulates protein synthesis, autophagy and cell growth.

Glutaminolysis: Metabolic pathway in which glutamine is converted to glutamate and then to α-ketoglutarate to fuel the tricarboxylic acid cycle and support anabolic processes.

References

1. An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer. Journal of Experimental & Clinical Cancer Research (2023).
2. Amino acid homeostasis and signalling in mammalian cells and organisms. Biochemical Journal (2017).
3. Deletion of Amino Acid Transporter ASCT2 (SLC1A5) Reveals an Essential Role for Transporters SNAT1 (SLC38A1) and SNAT2 (SLC38A2) to Sustain Glutaminolysis in Cancer Cells*. Journal of Biological Chemistry (2016).
4. The L-Type Amino Acid Transporter LAT1—An Emerging Target in Cancer. International Journal of Molecular Sciences (2019).
5. The Human SLC1A5 (ASCT2) Amino Acid Transporter: From Function to Structure and Role in Cell Biology. Frontiers in Cell and Developmental Biology (2018).
6. 4F2 (CD98) Heavy Chain Is Associated Covalently with an Amino Acid Transporter and Controls Intracellular Trafficking and Membrane Topology of 4F2 Heterodimer*. Journal of Biological Chemistry (1999).
7. LAT2, a New Basolateral 4F2hc/CD98-associated Amino Acid Transporter of Kidney and Intestine*. Journal of Biological Chemistry (1999).