MAPK Inhibition Requires Active RAC1 Signaling to Effectively Improve Iodide Uptake by Thyroid Follicular Cells

by Selleckchem | May 27 2023

The Sodium/Iodide Symporter (NIS) is responsible for the active transport of iodide into thyroid follicular cells. Differentiated thyroid carcinomas (DTCs) usually preserve the functional expression of NIS, allowing the use of radioactive iodine (RAI) as the treatment of choice for metastatic disease. However, a significant proportion of patients with advanced forms of TC become refractory to RAI therapy and no effective therapeutic alternatives are available. Impaired iodide uptake is mainly caused by the defective functional expression of NIS, and this has been associated with several pathways linked to malignant transformation. MAPK signaling has emerged as one of the main pathways implicated in thyroid tumorigenesis, and its overactivation has been associated with the downregulation of NIS expression. Thus, several strategies have been developed to target the MAPK pathway attempting to increase iodide uptake in refractory DTC. However, MAPK inhibitors have had only partial success in restoring NIS expression and, in most cases, it remained insufficient to allow effective treatment with RAI. In a previous work, we have shown that the activity of the small GTPase RAC1 has a positive impact on TSH-induced NIS expression and iodide uptake in thyroid cells. RAC1 is a downstream effector of NRAS, but not of BRAF. Therefore, we hypothesized that the positive regulation induced by RAC1 on NIS could be a relevant signaling cue in the mechanism underlying the differential response to MEK inhibitors, observed between NRAS- and BRAF-mutant tumors. In the present study, we found that the recovery of NIS expression induced through MAPK pathway inhibition can be enhanced by potentiating RAC1 activity in thyroid cell systems. The negative impact on NIS expression induced by the MAPK-activating alterations, NRAS Q61R and BRAF V600E, was partially reversed by the presence of the MEK 1/2 inhibitors AZD6244 and CH5126766. Notably, the inhibition of RAC1 signaling partially blocked the positive impact of MEK inhibition on NIS expression in NRAS Q61R cells. Conversely, the presence of active RAC1 considerably improved the rescue of NIS expression in BRAF V600E thyroid cells treated with MEK inhibitors. Overall, our data support an important role for RAC1 signaling in enhancing MAPK inhibition in the context of RAI therapy in DTC, opening new opportunities for therapeutic intervention.

Comments：

The Sodium/Iodide Symporter (NIS) is a protein responsible for transporting iodide into thyroid cells. Radioactive iodine (RAI) is used to treat metastatic differentiated thyroid carcinomas (DTCs), which usually preserve functional NIS expression. However, some DTCs become refractory to RAI therapy due to impaired iodide uptake caused by defective NIS expression. MAPK signaling is involved in thyroid tumorigenesis and is associated with NIS downregulation. Strategies to target MAPK pathway have been developed to increase iodide uptake, but with limited success. Previous work showed that RAC1, a protein downstream of NRAS, positively regulates TSH-induced NIS expression and iodide uptake. In the present study, it was found that potentiating RAC1 activity enhances the recovery of NIS expression induced through MAPK pathway inhibition in thyroid cells. MEK inhibitors AZD6244 and CH5126766 partially reversed the negative impact of NRAS Q61R and BRAF V600E mutations on NIS expression, and the presence of active RAC1 considerably improved the rescue of NIS expression in BRAF V600E thyroid cells treated with MEK inhibitors. Overall, these findings suggest that RAC1 signaling could enhance MAPK inhibition in the context of RAI therapy in DTC, opening new opportunities for therapeutic intervention.