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Cationic Amino Acid Transporter-1-Mediated Arginine Uptake Is Essential for Chronic Lymphocytic Leukemia Cell

Anke Werner1,2, Daniel Pieh2, Hakim Echchannaoui1

  • 1Third Department of Medicine (Hematology, Oncology, and Pneumology), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Frontiers in Oncology
|December 12, 2019
PubMed

Insights

Chronic lymphocytic leukemia (CLL) cells require extracellular arginine for growth and lack its endogenous synthesis. Inhibiting the arginine transporter CAT-1 halts proliferation and tumor growth, offering a potential new therapy for CLL.

Area of Science:

  • Oncology
  • Cancer Metabolism
  • Amino Acid Transport

Background:

  • Tumor cells often rely on external nutrients, including arginine, due to impaired endogenous synthesis.
  • Chronic lymphocytic leukemia (CLL) cells are identified as arginine-auxotrophic, lacking argininosuccinate synthase (ASS).
  • Arginine uptake in mammalian cells is facilitated by solute carrier (SLC) family transporters.

Purpose of the Study:

  • To investigate the dependence of chronic lymphocytic leukemia (CLL) cells on extracellular arginine.
  • To identify the specific arginine transporter(s) utilized by CLL cells.
  • To evaluate the therapeutic potential of targeting arginine transport in CLL.

Main Methods:

  • Assessed arginine dependence and ASS expression in primary and immortalized CLL cells.
  • Utilized lentiviral-mediated gene downregulation to inhibit the cationic amino acid transporter-1 (CAT-1) in HG3 CLL cells.
  • Evaluated the impact of CAT-1 inhibition on arginine uptake, proliferation, viability, and tumor growth in a murine xenograft model.

Main Results:

  • CLL cells were confirmed to be arginine-auxotrophic, expressing only CAT-1 for arginine import.
  • Downregulation of CAT-1 significantly reduced arginine uptake, proliferation, and viability of HG3 CLL cells.
  • In vivo, CAT-1 inhibition in CLL cells led to significant suppression of tumor growth in a murine model.

Conclusions:

  • Targeting extracellular arginine availability is a viable strategy for cancer therapy.
  • CAT-1 is the primary arginine importer in CLL cells and a critical dependency.
  • Inhibition of CAT-1 presents a promising therapeutic approach for treating chronic lymphocytic leukemia.
Keywords:
amino acid transporterargininechronic lymphocytic leukemianutrient restrictiontumor metabolism

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