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.
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.
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DOI：
10.1186/s13044-018-0057-6
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发表时间：
2018
期刊：
影响因子：
2.2
通讯作者：
Chen D
中科院分区：
文献类型：
--
作者：
Zhang H;Chen D
激活突变BRAFV 600 E是甲状腺乳头状癌（PTC）中常见的遗传事件。突变BRAFV 600 E与钠/碘同向转运体（NIS）的丢失和随后的放射性碘难治性（RAI）转移性疾病相关。BRAF V600 E抑制剂可通过抑制丝裂原活化蛋白激酶（MAPK）途径部分恢复NIS表达和碘摄取。已有研究报道BRAF V600 E抑制剂可重新激活MAPK信号。本研究旨在探讨BRAF V600 E抑制剂和MAPK信号抑制剂联合应用是否能更有效地增加NIS表达和RAI摄取，并探讨其机制。将BCPAP和K1细胞暴露于浓度递增的BRAF V600 E抑制剂PLX 4032（0.01 μM，0.1 μM，1 μM）或MEK/ERK抑制剂PD 98059（0.01 μM，0.1 μM，1 μM）或与其联合或/和存在3 mM高氯酸盐（ClO− 4）的条件下0-72 h。检测碘摄入量及BRAF、磷酸化ERK 1/2、NIS表达。单独使用PLX 4032或PD 98059不会诱导NIS表达，也不会增加BCPAP和K1细胞中的碘摄取。但PLX 4032和PD 98059联合处理可显著诱导BCPAP和K1细胞NIS表达并增加碘摄取。PLX 4032单独在早期抑制p-ERK表达，并在晚期重新激活p-ERK表达。然而，PLX 4032和PD 98059的组合处理完全抑制p-ERK表达。同时抑制BRAF V600 E和p-ERK可恢复NIS表达，并增加PTC细胞的碘摄取，这与p-ERK表达的抑制有关。这些结果需要临床试验来证实。
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. 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 (ClO− 4) for 0–72 h. Iodide uptake and expression of BRAF, phosphorylated (p) ERK1/2, NIS were detected. 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. 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.