TA1/LAT-1/CD98 light chain and system L activity, but not 4F2/CD98 heavy chain, respond to arginine availability in rat hepatic cells - Loss of response in tumor cells

Tumor associated gene-1/L amino acid transporter-1 (TA1/LAT-1) was recently identified as a light chain of the CD98 amino acid transporter and cellula r activation marker. Our previous studies with primary rat hepatocyte cultu res demonstrated that TA1 RNA levels were responsive to media amino acid co ncentrations, suggesting adaptive regulation, High level TA1 expression ass ociated with transformed cells also suggested a role in tumor progression. The present study examined the relationship of TA1/CD98 expression, adaptiv e response, and associated amino acid transport to neoplastic transformatio n using a panel of well characterized rat hepatic cell lines. We found 1) i ncreased expression of TA1 in response to amino acid depletion, specific fo r arginine but not glutamine; 2) loss of TA1 response to arginine in gamma- glutamyl transpeptidase-positive transformed and tumorigenic cells; 3) no a ppreciable response of 4F2/CD98 heavy chain to arginine levels; and 4) corr elation of system L amino acid transport activity in response to arginine w ith changes in TA1/LAT-1 mRNA but not total immunoreacting protein. Our res ults suggest this CD98 Light chain may act as an environmental sensor, resp onding to amino acid availability and that its regulation is complex. We hy pothesize that altered TA1 expression is an early event in hepatocarcinogen esis giving neoplastic cells a growth or survival advantage, particularly u nder conditions of limited amino acid availability.