LAT1, a subunit of heterodimeric
system L transporter responsible for transporting
neutral amino acids into cells, has been investigated in several
cancers because of its onco-fetal nature. Based on the studies of its functional inhibition, LAT1 has been proposed to be a new molecular target of a
cancer therapy. We have shown here that human
head and neck cancer cell line, Hep-2, expresses both LAT1 and 4F2hc, another subunit of
system L transporter. An inhibitor of system L, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic
acid (BCH), inhibited
leucine uptake by the cells. BCH administration or restriction of
essential amino acid leucine decreased viability of Hep-2 cells. Co-administration of
cisplatin with BCH reduced the viability of the cells more than either agent alone. When BCH treatment preceded
cisplatin administration, reduction in Hep-2 cell viability was additive. In contrast, when BCH was given after
cisplatin treatment, synergistic effect in decreasing the number of viable cells was obtained. BCH treatment decreased the phosphorylation of mTOR,
p70S6K and 4EBP1, suggesting that BCH enhanced anti-
tumor action of
cisplatin by inhibiting mTOR pathway. This potentiation may be used to reduce
cisplatin exposure to alleviate many unwanted toxicity of the
drug.