A mitochondrial glutamine transporter variant is a key regulator of glutamine metabolism and metabolic reprogramming in cancer cells, and targeting such transporters could be a new strategy for controlling tumor growth, Korean researchers reported online in the Dec. 19, 2019, edition of Cell Metabolism.  

The most abundant amino acid in blood, glutamine is crucial for the synthesis of tricarboxcylic acid (TCA) cycle metabolites, amino acids, nucleotides, fatty acids, antioxidants and ATP.  

Rapidly proliferating cancer cells are particularly dependent on glutamine, which is a key intermediate in the ATP energy generating TCA cycle.  

Moreover, as an intracellular signaling molecule, glutamine activates the mammalian target of rapamycin complex 1 (mTORC1) intracellular signaling pathway, promoting cell growth and metabolism.  

Cancer cells take up glutamine via several glutamine transporter families, among which the obligatory sodium-dependent transporter for neutral amino acids, SLC1A5, is known to be involved in various cancers.  

“We found that expression of the SLC1A5 variant was increased in pancreas cancer, but SLC1A5 is also higher in lung, colon and breast cancers, and in hepatocellular carcinoma tissues than in normal tissues,” said study leader Jung Min Han, an associate professor in the College of Pharmacy at Yonsei University in Incheon. 

Notably, SLC1A5 inhibition has been shown to impede glutamine uptake, leading to disturbance of mTORC1 signaling and activation of autophagy and cancer cell growth.  

“Although some researchers have developed SLC1A5 inhibitors to suppress glutamine metabolism in cancer cells, these are still in the preclinical developmental phase,” Han told BioWorld.  

The SLC1A5/ASCT2 antibody-drug conjugate MEDI-7247, (Astrazeneca plc) is in clinical trials for both hematological malignancies and solid tumors. 

For mitochondrial glutaminolysis, cytosolic glutamine must first diffuse across the outer mitochondrial membrane, then cross the inner mitochondrial membrane via the mitochondrial glutamine transporter.  

Although preliminary studies have shown the presence of a specific glutamine carrier system across the inner mitochondrial membrane, the exact nature of that remains unknown, despite its importance in cancer metabolism.  

In their new study, Han and his Yonsei University team established that a novel variant of the SLC1A5 gene played a critical role in cancer metabolic reprogramming by transporting glutamine into mitochondria.  

The SLC1A5 variant was shown to have an N-terminal targeting signal for mitochondrial localization, while hypoxia-induced gene expression of the variant was mediated by the hypoxia-inducible factor-2a (HIF-2a) protein.  

That is a significant finding, since “hypoxia in the tumor microenvironment typically occurs as the tumor mass grows, with hypoxic cancer cells exhibiting a variety of genetic and metabolic adaptations to survive, one of which is greater dependence on glutamine,” noted Han.  

However, “while the glutamine dependency of cancer cells is increased in hypoxia, we do not know how glutamine has metabolic significance in this condition.  

“In this paper, we have demonstrated how the SLC1A5 variant is regulated by the transcription factor, HIF-2a, induced by hypoxic conditions, suggesting cancer cells can use glutamine more effectively in hypoxia,” said Han.  

The researchers further showed that overexpression of the SLC1A5 variant mediated glutamine-induced ATP production and glutathione synthesis, while conferring resistance to the chemotherapeutic agent, gemcitabine, in established pancreatic cancer cell lines and patient-derived cancer cells.  

“Hypoxia also induces resistance to gemcitabine and we found that the SLC1A5 variant was involved in this hypoxia-induced gemcitabine resistance mechanism,” noted Han.  

Moreover, genetic knockdown of the SLC1A5 variant and its overexpression were both shown to alter cancer cell and tumor growth, supporting an oncogenic role for the variant.  

“Knockdown of the SLC1A5 variant resulted in disappearance of gemcitabine resistance in hypoxia, whereas expression of the SLC1A5 variant was increased in gemcitabine-resistant cell lines,” said Han. 

“We confirmed changes in cancer cell growth that occurred when knockdown or overexpression of the SLC1A5 variant by cell viability, clonogenic and in vivo xenograft assays.” 

Those previously unknown roles of the SLC1A5 variant may serve as a basis for the development of cancer therapies that inhibit mitochondrial glutamine metabolism, either alone or in combination with other cancer drug treatments. 

“Although there have been several reports on plasma membrane SLC1A5, this is the first study to identify the mitochondrial SLC1A5 variant as being a potential drug target,” said Han. 

“To date, no metabolic anticancer drug has been developed that targets glutamine dependency of cancer cells,” he said. 

A glutaminase inhibitor, telaglenastat (CB-839), is being developed by Calithera Biosciences Inc. and is now in phase II development.   

“Given that glutamine is essential for the growth of cancer cells, targeting mitochondrial glutamine transporters of cancer cells can be an effective anticancer strategy,” Han explained. 

“In this study, we have provided a new potential drug target by identifying cancer cell-specific metabolic vulnerability compared to normal cells and shown that the metabolic reprogramming induced by the SLC1A5 variant can affect the response of tumors to immune checkpoint inhibitors.  

“Therefore, our findings can be applied to developing a new combination strategy for cancer treatment,” Han said. 

In the future, he said, “because the SLC1A5 variant has not been identified in animals other than humans, for further in vivo experiments, we need to confirm the existence of SLC1A5 variant in mice and to investigate its role in normal physiology, while searching for compounds specifically targeting the SLC1A5 variant. 

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