|
|
L-type
amino acid transporter 1 as a potential molecular target in human
astrocytic tumors
Hiroshi
Nawashiro
1 *,
Naoki Otani
1,
Nariyoshi Shinomiya
2,
Shinji Fukui
1,
Hidetoshi Ooigawa
1,
Katsuji Shima
1,
Hirotaka Matsuo
3,
Yoshikatsu Kanai
4,
Hitoshi Endou
4
1Department
of Neurosurgery, National Defense Medical College, Tokorozawa,
Saitama, Japan. 2Department
of Microbiology, National Defense Medical College, Tokorozawa,
Saitama, Japan. 31st
Department of Physiology, National Defense Medical College, Tokorozawa,
Saitama, Japan. 4Department
of Pharmacology and Toxicology, Kyorin University School of Medicine,
Mitaka, Tokyo, Japan -- *Correspondence
to Hiroshi Nawashiro, Department of Neurosurgery, National Defense
Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan; Fax:
+81-4-2996-5207; Email: nawa1957@ndmc.ac.jp
-- Received: 2 October 2005; Accepted: 12 January 2006.
|
|
|
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.
Keywords: glioma, L-type amino
acid transporter (LAT1), BCH
|
