The Na(+)/I(-)
symporter (NIS)-mediated
iodide uptake is the basis for targeted radioiodine ablation of
thyroid cancers. However, NIS-mediated radioiodide uptake (RAIU) activity is often reduced in
thyroid cancers. As
mitogen activated protein kinase (MAPK) signaling pathway is activated in about 70% of
papillary thyroid carcinoma, we investigated whether
MEK (
MAPK kinase) inhibition will restore
NIS protein levels and NIS-mediated RAIU activity in RET/PTC oncogene-transformed thyroid cells. We found that
MEK inhibitor
PD98059 increased
NIS protein levels within 30 min of treatment. However, the increase of
NIS protein level was not accompanied with an increase in NIS-mediated RAIU activity, particularly at early time points of
PD98059 treatment.
PD98059 also decreased RAIU activity mediated by exogenous NIS in non-thyroid cells. The transient decrease of RAIU activity by
PD98059 in thyroid cells was not due to decreased NIS cell surface level, decreased NIS binding affinity for I(-) , or increased
iodide efflux. While
PD98059 moderately decreased Na(+)/K(+)-
ATPase activity,
ouabain titration indicates that the extent of decrease in Na(+)/K(+)-
ATPase activity is much greater than the extent of decrease in RAIU activity. Additionally, a decrease of Na(+)/K(+)-
ATPase activity was not accompanied with a decrease of
biotin uptake activity mediated by Na(+)-dependent multivitamin transporter. Since
PD98059 reduced V(max)- I(-) without decreasing NIS cell surface levels, it is most likely that
PD98059 decreases the turnover rate of
iodide transport with an yet to be identified mechanism.