Researchers from Germany starved breast cancer cells of amino acids, including methionine, and exploited their dependency on the amino acid transporter SLC6A14.
Cancerous tumors are greedy invaders. In order to sustain their signature high rate of growth, proliferation, and to increase their metabolic capacity, tumor cells demand more nutrients from the body, such as glucose and amino acids. One way that tumor cells elevate this intake of nutrients is by increasing the expression of genes that encode amino acid transporters. This knowledge provided new potential therapeutic targets for the authors of the cover paper for Oncotarget’s Vol 11, Issue #48.
“Targeting tumor metabolism has been explored as a strategy to inhibit tumor growth and proliferation due to the elevated metabolic requirements of cancer cells compared to their normal counterparts [1].”
Researchers from Germany organized the study, “Exploiting the metabolic dependencies of the broad amino acid transporter SLC6A14,” and targeted amino acids, including methionine, and the amino acid transporter SLC6A14 to starve breast cancer cells.
SLC6A14 Transports Amino Acids
Amino acid transporters are essential for the delivery of amino acids across the biological membrane to “feed” the tumor cells. In particular, SLC6A14 is an amino acid transporter that has features uniquely suited to meet the biological needs of tumor cells. This transporter has been found to be more frequently upregulated by tumor cells in colon, cervical, breast, and pancreatic cancer than in normal cells. Given this fact, the dependency that these various cancer cells have on SLC6A14 allowed the researchers to exploit the cancer cells without significantly affecting the normal cells.
“In this study, we extend the knowledge about SLC6A14 function by exploiting for the first time the combination of metabolic stress coupled to the transporter inhibition and elucidate the molecular responses elicited in breast cancer cells.”
The Study
Researchers analyzed a panel of breast cancer cell lines in vitro with induced metabolic stress, including amino acid starvation and SLC6A14 deletion. They found that SLC6A14 expression levels were increased in the absence of multiple amino acids (significantly in the absence of methionine), which suggests that amino acids may be responsible for an increase in gene expression. The restriction of methionine has been shown to increase sensitivity of chemotherapeutic agents and is essential for cellular methylation reactions.
“Interestingly, we found that SLC6A14 expression was mostly affected by the starvation of hydrophobic and aromatic amino acids, for which the transporter has the highest affinity [10]. This group comprises 10 different amino acids, among which starvation of methionine showed the highest impact on SLC6A14 expression.”
Under normal cell culture conditions, the genetic inhibition of SLC6A14 alone does not induce cell death or impact cell proliferation. However, inside the stress induced environment with both methionine deprived and SLC6A14 inhibited, the researchers observed that AMPK was activated—an enzyme and energy stress sensor.
“AMPK’s role in tumorigenesis is context-dependent and both pro- and anti-tumorigenic properties have been linked to its function [39].”
Conclusion
Under the context of methionine starvation and SLC6A14 deletion, AMPK activation supported genetic inhibition and induced tumor cell death. The depletion of AMPK and SLC6A14 led to an increase in tumor cell death when combined with methionine starvation. The researchers suggest that the combined targeting of SLC6A14 and AMPK is a viable therapeutic approach to starve tumor cells. They also acknowledge that additional in vivo studies should be conducted.
Click here to read the full scientific paper, published in Oncotarget.
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