A recent Scientific Reports study identified a novel amino acid transporter-based therapeutic target for pancreatic ductal adenocarcinoma (PDAC).
Study: Amino acid transporter SLC38A5 is a tumor promoter and a novel therapeutic target for pancreatic cancer. Image Credit: mi_viri/Shutterstock.com
PDAC cells have an elevated proliferation capacity and are in significant demand for nutrients, i.e., amino acids, sugars, and lipids. Amino acids are particularly associated with cancer growth.
The nutrient requirement of PDAC cells is typically met through upregulating selective amino acid transporters.
Although essential amino acids are not synthesized de novo and must be obtained from external sources, non-essential amino acids can be endogenously generated through precursors.
Since the increased demand for non-essential amino acids is not met, cancer cells rely on extracellular sources. This observation highlights the importance of amino acid transporters for the cancer cells.
The role of SLC38A5, an amino acid transporter
The current study sought to investigate SLC38A5 (SN2/SNAT5), a sodium-coupled neutral amino acid transporter, for its connection to PDAC. SLC38A5 transports glutamine, asparagine, methionine, glycine, and serine.
Functionally, this amino acid transporter transfers the amino acid substrate and Na+ in one direction by coupling to the transfer of H+ in the opposite direction.
A limited number of studies have focussed on the association between SLC38A5 and cancer manifestation. The current study sought to address the research gap and assess the role of SLC38A5 in PDAC proliferation and growth.
Cancer cells generate a significant amount of lactic acid, which subsequently increases H+ levels inside the cells. SLC38A5 can concentrate on amino acid substrates intracellularly and simultaneously remove H+ from cancerous cells. As a result, intracellular acidification is prevented.
Furthermore, an induction of micropinocytosis is also observed, which results from an increase in pH in the vicinity of the plasma membrane of cells on the cytoplasmic side.
It must be noted that macropinocytosis is a key nutrient scavenging mechanism for PDAC, which transfers glutamine for glutaminolysis. Typically, all cancerous cells are glutamine-addicted.
The current study demonstrated the critical role of SLC38A5 in PDAC growth and proliferation. Experimental observations revealed that SLC38A5 plays an important part in inducing a sub-population of α-cells that triggers the development of pancreatic neuroendocrine tumors (PNETs).
Consistent with the observation of this study, a previous study indicated the role of SLC38A5 in inducing macropinocytosis in Triple-Negative Breast Cancer (TNBC). Considering the present and past study observations, SLC38A5 has been identified as a potential tumor promoter.
PDAC growth is attenuated by SLC38A5 knockout (KO). Furthermore, metabolomic data revealed a significant reduction in many amino acids, i.e., SLC38A5 KO and non-transportable ones.
Although many SLC38A5 substrates were downregulated, glycine and glutamine remained upregulated in PDAC. This study also demonstrated that SLC38A5 recognizes cysteine, alanine, isoleucine, valine, threonine, proline, and phenylalanine as additional substrates. This resulted in a reduction in amino acid levels in the KO tumors.
SLC38A5 KO also resulted in mTORC1 inhibition. Recent studies have shown that besides arginine, leucine, and methionine, mTORC1 is also activated by asparagine, histidine, glutamine, serine, threonine, alanine, and valine.
Since many of these amino acids are SLC38A5 substrates, it is clear why the mTORC1 pathway was suppressed in the KO tumor samples. KO of SLC38A5 reduced the expression of other amino acid transporters (AATs). It must also be noted that SLC43A2/LAT4 was upregulated in the KO tumors.
SLC38A5 KO greatly downregulates OXPHOS-associated genes and proteins. It leads to serious metabolic crises, including mitochondrial respiration and glycolysis inhibition.
Consistent with the findings of this study, a previous study has shown that deletion of SLC38A2 causes a significant compartmentalized metabolic crisis in the PDAC cells.
The current study revealed that SLC38A5 is significantly upregulated in PDAC. This overexpression of SLC38A5 at the mRNA level causes poor survival in PDAC patients. A CRISPR/Cas9-mediated knockdown experiment revealed the tumor-promoting role of SLC38A5.
Genomics and metabolomics studies indicated that SLC38A5 deletion leads to a decrease in numerous amino acid substrates of SLC38A5 and inactivation of a fundamental mitochondrion process, namely, OXPHOS.
Furthermore, SLC38A5 deletion also causes inhibition of the mTORC1 signaling pathway, along with glycolysis and mitochondrial respiration.
Considering the experimental findings of this study, SLC38A5 has been identified as a key promoter of PDAC. Therefore, this could be used as a potential therapeutic target to develop novel treatments for PDAC.