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.
Highlights
One of the hallmarks of tumors is their deregulated metabolism
Grouping the samples based on the major breast cancer subtypes defined by the PAM50 gene expression signature [13, 14], we observed the highest levels of SLC6A14 expression in the basal-like and in the normal-like subtypes (Figure 1A)
SLC6A14 expression has been reported to be correlated with the estrogen receptor (ER) status [16], we did not find a significant correlation between the two variables in the tested breast cancer cell lines (P-value = 0.1274, Mann-Whitney U test) or in the breast tumors (Supplementary Figure 1A)
Summary
Cancer cells typically have a high demand for nutrients such as glucose and amino acids [1]. Consistent with the idea that the function of the amino acid transporters can be more critical for the maintenance of tumor cells, several amino acid transporters are reported to be overexpressed in a wide spectrum of tumors [3, 4]. In breast cancer, the metabolism of non-essential amino acids is found to be altered [5] and the expression of amino acid transporters correlates with tumor growth and progression [6,7,8]. Approximately 50 amino acid transporters have been identified and distinguished based on their subcellular localization (plasma membrane, mitochondria, lysosomes), their substrate specificity and their mechanism of transport [9]
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