L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors.
L-type amino acid transporter 1 (LAT1) is a Na+-independent neutral amino acid transport agency and essential for the transport of large neutral amino acids. LAT1 has been identified as a light chain of the CD98 heterodimer from C6 glioma cells. LAT1 also corresponds to TA1, an oncofetal antigen that is expressed primarily in fetal tissues and cancer cells. We have investigated for the first time, the expression of the transporter in the human primary astrocytic tumor tissue from 60 patients. LAT1 is unique because it requires an additional single membrane spanning protein, the heavy chain of 4F2 cell surface antigen (4F2hc), for its functional expression. 4F2hc expression was also determined by immunohistochemistry. Kaplan-Meier analyses demonstrated that high LAT1 expression correlated with poor survival for the study group as a whole (p<0.0001) and for those with glioblastoma multiforme in particular (p=0.0001). Cox regression analyses demonstrated that LAT1 expression was one of significant predictors of outcome, independent of all other variables. On the basis of these findings, we also investigated the effect of the specific inhibitor to LAT1, 2-aminobicyclo-2 (2,2,1)-heptane-2-carboxylic acid (BCH), on the survival of C6 glioma cells in vitro and in vivo using a rat C6 glioma model. BCH inhibited the growth of C6 glioma cells in vitro and in vivo in a dose-dependent manner. Kaplan-Meier survival data of rats treated with BCH were significant. These findings suggest that LAT1 could be one of the molecular targets in glioma therapy.
Department of Neurosurgery, National Defense Medical College, Tokorozawa, Saitama, Japan. nawa1957@ndmc.ac.jp
Hiroshi
H
Nawashiro
Naoki
N
Otani
Nariyoshi
N
Shinomiya
Shinji
S
Fukui
Hidetoshi
H
Ooigawa
Katsuji
K
Shima
Hirotaka
H
Matsuo
Yoshikatsu
Y
Kanai
Hitoshi
H
Endou
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000598:Amino Acids, Cyclic / Q000494:pharmacology; D000818:Animals; D001254:Astrocytoma / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D005260:Female; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000032:analysis; D005910:Glioma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D027283:Large Neutral Amino Acid-Transporter 1 / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis; D015996:Survival Rate
D000598:Amino Acids, Cyclic; D027282:Fusion Regulatory Protein 1, Heavy Chain; D027283:Large Neutral Amino Acid-Transporter 1; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid