L-type amino acid transporter-1 overexpression and melphalan sensitivity in Barrett's adenocarcinoma.
The L-type amino acid transporter-1 (LAT-1) has been associated with tumor growth. Using cDNA microarrays, overexpression of LAT-1 was found in 87.5% (7/8) of esophageal adenocarcinomas relative to 12 Barrett's samples (33% metaplasia and 66% dysplasia) and was confirmed in 100% (28/28) of Barrett's adenocarcinomas by quantitative reverse transcription polymerase chain reaction. Immunohistochemistry revealed LAT-1 staining in 37.5% (24/64) of esophageal adenocarcinomas on tissue microarray. LAT-1 also transports the amino acid-related chemotherapeutic agent, melphalan. Two esophageal adenocarcinoma and one esophageal squamous cell line, expressing LAT-1 on Western blot analysis, were sensitive to therapeutic doses of melphalan (P <.001). Simultaneous treatment with the competitive inhibitor, BCH [2-aminobicyclo-(2,1,1)-heptane-2-carboxylic acid], decreased sensitivity to melphalan (P <.05). In addition, confluent esophageal squamous cultures were less sensitive to melphalan (P <.001) and had a decrease in LAT-1 protein expression. Tumors from two esophageal adenocarcinoma cell lines grown in nude mice retained LAT-1 mRNA expression. These results demonstrate that LAT-1 is highly expressed in a subset of esophageal adenocarcinomas and that Barrett's adenocarcinoma cell lines expressing LAT-1 are sensitive to melphalan. LAT-1 expression is also retained in cell lines grown in nude mice providing a model to evaluate melphalan as a chemotherapeutic agent against esophageal adenocarcinomas expressing LAT-1.
Lin
Jules
J
Section of General Thoracic Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Raoof
Duna A
DA
Thomas
Dafydd G
DG
Greenson
Joel K
JK
Giordano
Thomas J
TJ
Robinson
Gregory S
GS
Bourner
Maureen J
MJ
Bauer
Christopher T
CT
Orringer
Mark B
MB
Beer
David G
DG
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D026962:Amino Acid Transport System ASC / Q000096:biosynthesis*; D000818:Animals; D001471:Barrett Esophagus / Q000188:drug therapy / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008558:Melphalan / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D026962:Amino Acid Transport System ASC; D012333:RNA, Messenger; C498848:SLC1A4 protein, human; C498847:Slc1a4 protein, mouse; D008558:Melphalan