Τετάρτη 10 Οκτωβρίου 2018

Synergistic inhibition of MEK/ERK and BRAF V600E with PD98059 and PLX4032 induces sodium/iodide symporter (NIS) expression and radioiodine uptake in BRAF mutated papillary thyroid cancer cells

Abstract

Background and Aims

The activating mutation BRAFV600E is a frequent genetic event in papillary thyroid carcinomas (PTC). Mutation BRAFV600E is associated with the loss of a sodium/iodine symporter (NIS), and subsequent radioiodide-refractory (RAI) metastatic disease. Use of BRAF V600E inhibitors could partly restore NIS expression and Iodide uptake by inhibition of mitogen-activated protein kinase (MAPK) pathway. Previous study has reported that the BRAF V600E inhibitors could re-activate MAPK signals. In the present study, we investigated whether the combination treatment of BRAF V600E inhibitor and MAPK signal inhibitor could more effectively increase NIS expression and RAI uptake, and explore the mechanisms.

Methods

BCPAP and K1 cells were exposed to increasing concentrations of BRAF V600E inhibitor PLX4032 (0.01 μM, 0.1 μM, 1 μM) or MEK/ERK inhibitor PD98059 (0.01 μM, 0.1 μM, 1 μM) or with their association or/and in the presence of 3 mM perchlorate (ClO4) for 0–72 h. Iodide uptake and expression of BRAF, phosphorylated (p) ERK1/2, NIS were detected.

Results

PLX4032 or PD98059 alone did not induce NIS expression and increase Iodide uptake in BCPAP and K1 cells. But combined treatment of PLX4032 and PD98059 significantly induce NIS expression and increase Iodide uptake in BCPAP and K1 cells. PLX4032 alone inhibited p-ERK expression at early time, and re-activated p-ERK expression at late time. However, combined treatment of PLX4032 and PD98059 completely inhibited p-ERK expression.

Conclusion

Simultaneously suppressing BRAF V600E and p-ERK restored NIS expression and increase Iodide uptake in PTC cells, which was associated the inhibition of p-ERK expression. The results warrants clinical trials to confirm.



from #Head and Neck by Sfakianakis via simeraentaxei on Inoreader https://ift.tt/2C8HxMw

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου

Σημείωση: Μόνο ένα μέλος αυτού του ιστολογίου μπορεί να αναρτήσει σχόλιο.