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  • Title: Oncogenicity of L-type amino-acid transporter 1 (LAT1) revealed by targeted gene disruption in chicken DT40 cells: LAT1 is a promising molecular target for human cancer therapy.
    Author: Ohkawa M, Ohno Y, Masuko K, Takeuchi A, Suda K, Kubo A, Kawahara R, Okazaki S, Tanaka T, Saya H, Seki M, Enomoto T, Yagi H, Hashimoto Y, Masuko T.
    Journal: Biochem Biophys Res Commun; 2011 Mar 25; 406(4):649-55. PubMed ID: 21371427.
    Abstract:
    L-type amino-acid transporter 1 (LAT1) is the first identified light chain of CD98 molecule, disulfide-linked to a heavy chain of CD98. Following cDNA cloning of chicken full-length LAT1, we have constructed targeting vectors for the disruption of chicken LAT1 gene from genomic DNA of chicken LAT1 consisting of 5.4kb. We established five homozygous LAT1-disrupted (LAT1(-/-)) cell clones, derived from a heterozygous LAT1(+/-) clone of DT40 chicken B cell line. Reactivity of anti-chicken CD98hc monoclonal antibody (mAb) with LAT1(-/-) DT40 cells was markedly decreased compared with that of wild-type DT40 cells. All LAT1(-/-) cells were deficient in L-type amino-acid transporting activity, although alternative-splice variant but not full-length mRNA of LAT1 was detected in these cells. LAT1(-/-) DT40 clones showed outstandingly slow growth in liquid culture and decreased colony-formation capacity in soft agar compared with wild-type DT40 cells. Cell-cycle analyses indicated that LAT1(-/-) DT40 clones have prolonged cell-cycle phases compared with wild-type or LAT1(+/-) DT40 cells. Knockdown of human LAT1 by small interfering RNAs resulted in marked in vitro cell-growth inhibition of human cancer cells, and in vivo tumor growth of HeLa cells in athymic mice was significantly inhibited by anti-human LAT1 mAb. All these results indicate essential roles of LAT1 in the cell proliferation and occurrence of malignant phenotypes and that LAT1 is a promising candidate as a molecular target of human cancer therapy.
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