c-Myc is crucial for the expression of LAT1 in MIA Paca-2 human pancreatic             cancer cells.
Tumor cells take up a massive amount of nutrition compared to normal cells             for increased metabolism. Therefore, special transporters for organic materials             are required to satisfy the powerful consumption of nutrition in tumor cells.             L-type amino acid transporter 1 (LAT1) incorporates large neutral amino acids,             most of which are also categorized as essential amino acids, into cells in a Na+-independent             manner. Because of its high expression levels in a variety of cancer cells, it             is speculated that LAT1 functions as a key transporter for highly effective delivery             of essential amino acids into cancer cells. In this regard, LAT1 inhibitor is             expected to have clinical benefit for cancer therapy. However, the molecular mechanism             of enrichment of LAT1 in cancer cells remains poorly understood. Here, we show             that a proto-oncogene, c-Myc, is a critical positive regulator of LAT1 expression             in MIA Paca-2 human pancreatic cancer cells. The uptake of leucine, a representative             neutral amino acid, was strictly dependent on LAT1 in MIA Paca-2 cells, and siRNA-mediated             knockdown of LAT1 inhibited cell proliferation. Diminished c-Myc expression with             siRNA resulted in severe reduction of LAT1 protein levels as well as mRNA levels,             which, in turn, led to a significant defect of leucine incorporation. The LAT1             promoter has a canonical c-Myc binding sequence and overexpression of c-Myc increased             LAT1 promoter activity, whereas mutation of c-Myc binding site diminished this             effect. Our results suggest biological significance of LAT1 in tumor growth and             molecular machinery that could explain why LAT1 is preferentially expressed in             cancer cells.
Department of Pharmacology and Toxicology, Dokkyo Medical University                     School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan.
Keitaro
K
Hayashi
Promsuk
P
Jutabha
Hitoshi
H
Endou
Naohiko
N
Anzai
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016384:Consensus Sequence; D015536:Down-Regulation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D010190:Pancreatic Neoplasms; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034741:RNA, Small Interfering
D027283:Large Neutral Amino Acid-Transporter 1; C000715470:MAS1 protein, human; C489427:MYC protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D008156:Luciferases; D007930:Leucine