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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.01268

Cationic amino acid transporter-1-mediated arginine uptake is essential for chronic lymphocytic leukemia cell proliferation and viability

 Anke Werner1, Daniel Pieh1, Hakim Echchannaoui1, Johanna Rupp1,  Krishnaraj Rajalingam1, Matthias Theobald1,  Ellen I. Closs1 and  Markus Munder2*
  • 1Johannes Gutenberg University Mainz, Germany
  • 2Third Department of Medicine (Hematology, Oncology, and Pneumology), Johannes Gutenberg University Mainz, Germany

Interfering with tumor metabolism by specifically restricting the availability of extracellular nutrients is a rapidly emerging field of cancer research. A variety of tumor entities depend on the uptake of the amino acid arginine since they have lost the ability to synthesize it endogenously, that is they do not express the rate limiting enzyme for arginine synthesis, argininosuccinate synthase (ASS). Arginine transport through the plasma membrane of mammalian cells is mediated by eight different transporters that belong to two solute carrier (SLC) families. In the present study we found that the proliferation of primary as well as immortalized chronic lymphocytic leukemia (CLL) cells depends on the availability of extracellular arginine and that primary CLL cells do not express ASS and are therefore arginine-auxotrophic. The cationic amino acid transporter-1 (CAT-1) was the only arginine importer expressed in CLL cells. Lentiviral-mediated downregulation of the CAT-1 transporter in HG3 CLL cells significantly reduced arginine uptake, abolished cell proliferation and impaired cell viability. In a murine CLL xenograft model, tumor growth was significantly suppressed upon induced downregulation of CAT-1 in the CLL cells. Our results suggest that inhibition of CAT-1 is a promising new therapeutic approach for CLL.

Keywords: tumor metabolism, Arginine, amino acid transporter, chronic lymphocytic leukemia, Nutrient restriction

Received: 13 Sep 2019; Accepted: 01 Nov 2019.

Copyright: © 2019 Werner, Pieh, Echchannaoui, Rupp, Rajalingam, Theobald, Closs and Munder. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Markus Munder, Johannes Gutenberg University Mainz, Third Department of Medicine (Hematology, Oncology, and Pneumology), Mainz, Germany, munder@uni-mainz.de