Introduction: Glutamine is an amino acid that is used in the biosynthesis of proteins, and is considered to be an important intermediate in many metabolic processes of cancer cells. It has been reported that the expression level of SLC1A5 mRNA were high in several cancers, and SLC1A5 inhibition suppressed the progression of cancer cells in non-small cell lung cancer and squamous cell carcinoma. On the other hand, it has not been fully investigated in renal cell carcinoma (RCC).
Previous studies have investigated the expression level of SLC1A5 mRNA in each cancer type, and it has been confirmed that the expression level is also high in renal cell carcinoma (RCC). In addition, it has been previously reported that in RCC, a tumor growth effect is observed depending on the concentration of glutamine, which was not found in other amino acids.
Methods: First, the clinical significance of SLC1A5 in RCC was analyzed using The Cancer Genome Atlas (TCGA) database. We then performed a loss-of-function assay for SLC1A5 with si-RNA or inhibitor (V9302) in human RCC cell lines. In addition, we checked if V9302 showed the antitumor effect in vivo or not using a Xenograft model. Finally, the mechanism of antitumor effect by SLC1A5 inhibition was investigated through senescence-associated ß-galactosidase (SA-ß-gal) activity staining.
Results: According to our analyses using database such as TCGA, we found that the expression level of SLC1A5 mRNA was significantly higher in RCCs than in normal kidneys. Furthermore, SLC1A5 high expression was associated with RCC advanced stage, and the high expression group (n = 261) of SLC1A5 had a significantly worse prognosis than the low expression group (n = 261) (P = 0.000395). We also found that glutamine starvation suppressed RCC cell proliferation in a dose-dependent manner, which were not observed in other amino acids such as asparagine, arginine and kynurenine. Suppression of SLC1A5 with si-RNA or V9302 in vitro significantly suppressed tumor growth, invasion, and migration. In addition, SLC1A5 inhibition with V9302 in vivo significantly suppressed tumor growth by more than half compared to controls (P = 0.0041). As a mechanism in anti-tumor effect by SLC1A5 inhibition, we found that inhibition of glutamine uptake promoted cellular senescence through p21 induction.
Conclusions: It was confirmed that inhibition of glutamine transport via SLC1A5 suppressed tumor growth, infiltration, and migration in RCC through cellular senescence. Our finding may lead to a better understanding of RCC and the development of new therapeutic strategies for RCC.
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