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Oncotarget: Exploiting the metabolic dependencies of the broad amino acid transporter SLC6A14

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Oncotarget recently published "Exploiting the metabolic dependencies of the broad amino acid transporter SLC6A14" which reported that 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.

The Oncotarget authors 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 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.

"Suggesting that combined targeting of SLC6A14 and AMPK can be exploited as a therapeutic approach to starve tumor cells"

Dr. Balca R. Mardin from The BioMed X Institute said, "One of the hallmarks of tumors is their deregulated metabolism."

Since amino acids are used for the synthesis of macromolecules required for sustaining the accelerated growth of tumor cells, blocking the amino acid transporters may present as a viable therapeutic option, leading to amino acid starvation selectively in tumor cells.

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.

For instance, in breast cancer, the metabolism of non-essential amino acids is found to be altered and the expression of amino acid transporters correlates with tumor growth and progression.

The amino acid transporter SLC6A14 is a highly concentrative symporter which makes use of the sodium and chloride gradient to uptake amino acids.

Figure 4: Evaluation of stress response markers in the absence of amino acid transporters. (A) Immunoblots of inducible MDA-MB-468 KO cell lines upon metabolic stress. Cells were induced with doxycycline for 4 days, plated and cultured for 24 h or 72 h in the indicated media: Full = complete medium; Starv = medium without aromatic and hydrophobic amino acids; - Met = medium without methionine. (B) Immunoblot quantification. Boxplots represent values from three independent experiments. In the boxplots, centerlines mark the medians, box limits indicate the 25th and 75th percentiles, and whiskers extend to 5th and 95th percentiles.

Although in vitro studies have revealed variable affinities of each substrate, SLC6A14 can transport the highest range of amino acids compared to all the other amino acid transporters.

The Mardin Research Team concluded in their Oncotarget Research Paper that Increased levels of phosphorylated AMPK in SLC6A14 KO cells challenged with amino acid stress prompted us to test whether blocking AMPK activation can be a vulnerability under these conditions.

For this experiment, the authors transfected gRNAs targeting PRKAA1 and PRKAA2, which encode AMPK α1 and AMPK α2 subunits respectively, in our isogenic cell lines.

Consistent with the fact that SLC6A14 KO alone induces a mild activation of AMPK, they observed a moderate decrease in the cell proliferation rate only in the SLC6A14 KO cell line.

This combination seems to be most pronounced upon SLC6A14 KO, in line with their previous results demonstrating the highest increase of AMPK activation in SLC6A14 KO cells.

Altogether, the data indicate that AMPK activation is a metabolic vulnerability in SLC6A14-deficient cells that can be exploited as a therapeutic approach to drive unbalanced metabolism in starved tumor cells.

DOI - https://doi.org/10.18632/oncotarget.27758

Full text - https://www.oncotarget.com/article/27758/text/

Correspondence to - Balca R. Mardin - mardin@bio.mx

Keywords - SLC6A14, metabolic stress, transcriptional regulation, methionine, AMPK

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