Abstract
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Objectives: To investigate the inhibitory effect of BI-847325, a novel MEK inhibitor, on the proliferation of BRAFV600E mutant thyroid carcinoma cell line BCPAP and the expression regulation of apoptotic proteins as well as sodium/iodide symporter (NIS).
Methods: BCPAP cells were treated for 48 h with different concentrations of BI-847325. The effect of BI-847325 on the proliferation of BCPAP cells was investigated by the CCK-8 assay; the apoptosis of BCPAP cells was evaluated by the flow cytometry; the activation level of MEK and its downstream apoptotic proteins and NIS were analyzed by Western Blotting. BCPAP cells were treated with 5 μM vemurafenib for 2 weeks to obtain vemurafenib-resistant BCPAP cells. The effect of BI-847325 on the proliferation of vemurafenib-resistant BCPAP cells was investigated by the CCK-8 assay, and the activation level of MEK was analyzed by Western Blotting.
Results: (1) BI-847325 inhibited the proliferation of BCPAP cells and the IC50 of BI-847325 for 48h was 0.46 μM. (2) BI-847325 induced apoptosis of BCPAP cells, and the apoptosis rate was (26.41±2.23)% when the concentration was 0.4 μM. (3) BI-847325 suppressed the activation level of MEK 1/2,ERK 1/2, and adjusted the expression of BIM, BAX and BCL-2. (4) BI-847325 up-regulated the expression of sodium/iodide symporter (NIS). (5) BI-847325 inhibited the proliferation of vemurafenib-resistant BCPAP cells and the IC50 of BI-847325 for 48 h was 0.55 μM. Furthermore, reactivated MEK/ERK were suppressed by BI-847325 in vemurafenib-resistant BCPAP cells.
Conclusions: BI-847325 induced the apoptosis of BCPAP and vemurafenib-resistant BCPAP cells by inhibiting the activation level of MEK/ERK; BI-847325 up-regulated the expression of NIS, which might increase the 131I uptake of BCPAP cells. BI-847325 might be a potential thyroid cancer targeted therapy drug. Key words: BI-847325, thyroid carcinoma, apoptosis, MEK/ERK, NIS
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