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MEK signaling modulates sodium iodide symporter at multiple levels and in a paradoxical manner
Douangsone D Vadysirisack1, Anjli Venkateswaran, Zhaoxia Zhang
1Integrated Biomedical Science Graduate Program, The Ohio State University, Columbus, Ohio 43210, USA.
Abstract:
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.
Insights
MEK inhibitor PD98059 increased sodium-iodide symporter (NIS) protein levels in thyroid cancer cells. However, it did not restore radioiodide uptake activity, suggesting a complex regulatory mechanism beyond protein levels.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Sodium-iodide symporter (NIS)-mediated iodide uptake is crucial for radioiodine therapy in thyroid cancer.
- Reduced NIS activity is a common challenge in treating thyroid cancers.
- The MAPK signaling pathway is frequently activated in papillary thyroid carcinoma.
Purpose of the Study:
- To investigate if MEK (MAPK kinase) inhibition can restore NIS protein levels and radioiodide uptake activity (RAIU) in thyroid cancer cells.
- To explore the effects of MEK inhibition on NIS function and related cellular processes.
Main Methods:
- Utilized RET/PTC oncogene-transformed thyroid cells.
- Administered MEK inhibitor PD98059 and assessed NIS protein levels and RAIU.
- Evaluated NIS cell surface expression, iodide binding affinity, and iodide efflux.
- Measured Na(+)/K(+)-ATPase activity and biotin uptake.
Main Results:
- PD98059 rapidly increased NIS protein levels but did not enhance RAIU, especially at early time points.
- PD98059 decreased RAIU mediated by exogenous NIS in non-thyroid cells.
- The reduction in RAIU was not attributed to decreased NIS cell surface levels, binding affinity, or increased efflux.
- PD98059 moderately reduced Na(+)/K(+)-ATPase activity, but this decrease was disproportionately larger than the observed decrease in RAIU.
Conclusions:
- MEK inhibition by PD98059 increases NIS protein levels but fails to restore NIS-mediated radioiodide uptake in thyroid cancer cells.
- The drug likely reduces iodide transport turnover rate via an unidentified mechanism, independent of NIS cell surface expression.
- Further research is needed to elucidate the precise mechanism by which MEK inhibition affects NIS transport function.
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