Oncotarget

Research Papers:

Exploiting the metabolic dependencies of the broad amino acid transporter SLC6A14

Francesca R. Dejure, Joachim Butzer, Ralph K. Lindemann and Balca R. Mardin _

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Oncotarget. 2020; 11:4490-4503. https://doi.org/10.18632/oncotarget.27758

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Abstract

Francesca R. Dejure1, Joachim Butzer1, Ralph K. Lindemann2 and Balca R. Mardin1

1 BioMed X Institute (GmbH), Heidelberg, Germany

2 Translational Innovation Platform Oncology, Merck KGaA, Darmstadt, Germany

Correspondence to:

Balca R. Mardin,email: mardin@bio.mx

Keywords: SLC6A14; metabolic stress; transcriptional regulation; methionine; AMPK

Received: May 09, 2020     Accepted: September 10, 2020     Published: December 01, 2020

Copyright: © 2020 Dejure et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Tumor cells typically enhance their metabolic capacity to sustain their higher rate of growth and proliferation. One way to elevate the nutrient intake into cancer cells is to increase the expression of genes encoding amino acid transporters, which may represent targetable vulnerabilities. Here, we study the regulation and function of the broad amino acid transporter SLC6A14 in combination with metabolic stress, providing insights into an uncharacterized aspect of the transporter activity. We analyze the pattern of transcriptional changes in a panel of breast cancer cell lines upon metabolic stress and found that SLC6A14 expression levels are increased in the absence of methionine. Methionine deprivation, which can be achieved via modulation of dietary methionine intake in tumor cells, in turn leads to a heightened activation of the AMP-activated kinase (AMPK) in SLC6A14-deficient cells. While SLC6A14 genetic deficiency does not have a major impact on cell proliferation, combined depletion of AMPK and SLC6A14 leads to an increase in apoptosis upon methionine starvation, suggesting that combined targeting of SLC6A14 and AMPK can be exploited as a therapeutic approach to starve tumor cells.


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PII: 27758