Effects of targeting SLC1A5 on inhibiting gastric cancer growth and tumor development in vitro and in vivo

Aims To investigate the oncogenic effects of SLC1A5 on gastric cancer development in vitro and in vivo. Methods The expression level of SLC1A5 was detected in 70 gastric cancer paraffin-embedded tissues by immunohistochemistry and also was detected in gastric cancer cell lines by qRT-PCR and western blotting analysis. The effects of knockdown SLC1A5 were analyzed on cell proliferation, cell cycle, the ability of cell migration and invasion and growth signaling pathway in vitro. By using subcutaneous xenograft mouse, the importance of SLC1A5 expression was assessed for both successful engraftment and growth of gastric cancer cells in vivo. Results SLC1A5 was up-regulated in gastric cancer tissues and was correlated with malignant features such as deeper local invasion, higher lymph node metastasis, advanced TNM stages and higher Ki-67 expression. Knockdown SLC1A5 in gastric cancer cells suppressed cell proliferation, caused G0/G1 arrest and inhibited cell invasion as well as migration partly by inactivated mTOR/p-70S6K1 signaling pathway in vitro. Furthermore, in vivo experiments indicated that suppression of SLC1A5 could inhibit relative volume of xenografted tumor. Conclusions Our results suggested that SLC1A5 might be considered as a new biomarker and also as a potential therapeutic target in gastric cancer.

[1]  Quan-Yong Luo,et al.  Afamin promotes glucose metabolism in papillary thyroid carcinoma , 2016, Molecular and Cellular Endocrinology.

[2]  B. Evans,et al.  Synergism between Inositol Polyphosphates and TOR Kinase Signaling in Nutrient Sensing, Growth Control, and Lipid Metabolism in Chlamydomonas[OPEN] , 2016, Plant Cell.

[3]  F. Mulero,et al.  Targeting Tumor Mitochondrial Metabolism Overcomes Resistance to Antiangiogenics. , 2016, Cell reports.

[4]  M. Tsai,et al.  Fenofibrate Suppresses Oral Tumorigenesis via Reprogramming Metabolic Processes: Potential Drug Repurposing for Oral Cancer , 2016, International journal of biological sciences.

[5]  T. Oyama,et al.  Clinicopathological significance of LAT1 and ASCT2 in patients with surgically resected esophageal squamous cell carcinoma , 2016, Journal of surgical oncology.

[6]  N. Pavlova,et al.  The Emerging Hallmarks of Cancer Metabolism. , 2016, Cell metabolism.

[7]  P. Massion,et al.  Targeting SLC1a5‐mediated glutamine dependence in non‐small cell lung cancer , 2015, International journal of cancer.

[8]  Jeffrey W. Smith,et al.  Right on TARGET: glutamine metabolism in cancer , 2015, Oncoscience.

[9]  T. Oyama,et al.  Clinical significance of coexpression of L-type amino acid transporter 1 (LAT1) and ASC amino acid transporter 2 (ASCT2) in lung adenocarcinoma. , 2015, American journal of translational research.

[10]  T. Oyama,et al.  Expression of Amino Acid Transporters (LAT1 and ASCT2) in Patients with Stage III/IV Laryngeal Squamous Cell Carcinoma , 2015, Pathology & Oncology Research.

[11]  M. Gleave,et al.  Targeting ASCT2‐mediated glutamine uptake blocks prostate cancer growth and tumour development , 2015, The Journal of pathology.

[12]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[13]  Boris Ratnikov,et al.  Glutamate and asparagine cataplerosis underlie glutamine addiction in melanoma , 2015, Oncotarget.

[14]  Ali Masoudi-Nejad,et al.  Metabolic cancer biology: structural-based analysis of cancer as a metabolic disease, new sights and opportunities for disease treatment. , 2015, Seminars in cancer biology.

[15]  G. Qing,et al.  ATF4 and N‐Myc coordinate glutamine metabolism in MYCN‐amplified neuroblastoma cells through ASCT2 activation , 2015, The Journal of pathology.

[16]  N. Sunaga,et al.  Clinicopathological significance of ASC amino acid transporter‐2 expression in pancreatic ductal carcinoma , 2015, Histopathology.

[17]  J. Rasko,et al.  Targeting glutamine transport to suppress melanoma cell growth , 2014, International journal of cancer.

[18]  M. Scalise,et al.  Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health , 2014, Front. Chem..

[19]  T. Oyama,et al.  Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer , 2014, British Journal of Cancer.

[20]  J. Tamburini,et al.  Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia. , 2013, Blood.

[21]  Roopma Wadhwa,et al.  Gastric cancer—molecular and clinical dimensions , 2013, Nature Reviews Clinical Oncology.

[22]  P. Massion,et al.  SLC1A5 Mediates Glutamine Transport Required for Lung Cancer Cell Growth and Survival , 2012, Clinical Cancer Research.

[23]  David S. Wishart,et al.  HMDB 3.0—The Human Metabolome Database in 2013 , 2012, Nucleic Acids Res..

[24]  E. Gottlieb,et al.  Glutaminolysis activates Rag-mTORC1 signaling. , 2012, Molecular cell.

[25]  Michael Hummel,et al.  Supplementary Figure 3 , 2010 .

[26]  M. Hall,et al.  TOR Signaling in Growth and Metabolism , 2006, Cell.

[27]  C. Esslinger,et al.  Ngamma-aryl glutamine analogues as probes of the ASCT2 neutral amino acid transporter binding site. , 2005, Bioorganic & medicinal chemistry.

[28]  M. Hediger,et al.  The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects , 2004, Pflügers Archiv.

[29]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.