SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival.

Hassanein M, Hoeksema MD, Shiota M, Qian J, Harris BK, Chen H, Clark JE, Alborn WE, Eisenberg R, Massion PP
Clin Cancer Res. 2013 19 (3): 560-70

PMID: 23213057 · PMCID: PMC3697078 · DOI:10.1158/1078-0432.CCR-12-2334

PURPOSE - We have previously identified solute-linked carrier family A1 member 5 (SLC1A5) as an overexpressed protein in a shotgun proteomic analysis of stage I non-small cell lung cancer (NSCLC) when compared with matched controls. We hypothesized that overexpression of SLC1A5 occurs to meet the metabolic demand for lung cancer cell growth and survival.

EXPERIMENTAL DESIGN - To test our hypothesis, we first analyzed the protein expression of SLC1A5 in archival lung cancer tissues by immunohistochemistry and immunoblotting (N = 98) and in cell lines (N = 36). To examine SLC1A5 involvement in amino acid transportation, we conducted kinetic analysis of l-glutamine (Gln) uptake in lung cancer cell lines in the presence and absence of a pharmacologic inhibitor of SLC1A5, gamma-l-Glutamyl-p-Nitroanilide (GPNA). Finally, we examined the effect of Gln deprivation and uptake inhibition on cell growth, cell-cycle progression, and growth signaling pathways of five lung cancer cell lines.

RESULTS - Our results show that (i) SLC1A5 protein is expressed in 95% of squamous cell carcinomas (SCC), 74% of adenocarcinomas (ADC), and 50% of neuroendocrine tumors; (ii) SLC1A5 is located at the cytoplasmic membrane and is significantly associated with SCC histology and male gender; (iii) 68% of Gln is transported in a Na(+)-dependent manner, 50% of which is attributed to SLC1A5 activity; and (iv) pharmacologic and genetic targeting of SLC1A5 decreased cell growth and viability in lung cancer cells, an effect mediated in part by mTOR signaling.

CONCLUSIONS - These results suggest that SLC1A5 plays a key role in Gln transport controlling lung cancer cells' metabolism, growth, and survival.

MeSH Terms (24)

Adult Aged Amino Acid Transport System ASC Biological Transport Carcinoma, Non-Small-Cell Lung Carcinoma, Squamous Cell Cell Line, Tumor Cell Membrane Cell Proliferation Cell Survival Female G1 Phase Cell Cycle Checkpoints Gene Expression Glutamine Humans Lung Neoplasms Male Middle Aged Minor Histocompatibility Antigens Reactive Oxygen Species RNA Interference Sex Factors Signal Transduction TOR Serine-Threonine Kinases

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