TY - JOUR
T1 - Reverting iodine avidity of radioactive-iodine refractory thyroid cancer with a new tyrosine kinase inhibitor (K905-0266) excavated by high-throughput NIS (sodium iodide symporter) enhancer screening platform using dual reporter gene system
AU - Oh, Ji Min
AU - Kalimuthu, Senthilkumar
AU - Gangadaran, Prakash
AU - Baek, Se Hwan
AU - Zhu, Liya
AU - Lee, Ho Won
AU - Rajendran, Ramya Lakshmi
AU - Hong, Chae Moon
AU - Jeong, Shin Young
AU - Lee, Sang Woo
AU - Lee, Jaetae
AU - Ahn, Byeong Cheol
N1 - Publisher Copyright:
© Oh et al.
PY - 2018
Y1 - 2018
N2 - Radioactive-iodine (RAI) therapy is typically unprevailing as anaplastic thyroid cancer (ATC) management, owing to the decrease in the endogenous sodium iodide symporter (NIS) expression. Therefore, new strategies for NIS re-induction are required to improve the efficacy of RAI therapy in ATC. In this study, we developed a novel high-throughput NIS enhancer screening platform using a dual reporter gene system to identify a potent tyrosine kinase inhibitor (TKI) and selected a new hit compound, K905-0266 TKI. The effects of K905-0266 TKI treatment was validated as RAI accumulation, changes in signalling pathway related to thyroid pathogenesis, and cytotoxicity of RAI depending on re-induction of endogenous NIS expression in ATC. Furthermore, we evaluated enhancement of NIS promoter and therapeutic efficacy of RAI in ATC tumour xenograft mice. After K905-0266 TKI treatment, the expression of endogenous NIS was significantly increased, while phosphorylated- ERK was decreased. In addition, the thyroid-metabolising protein expressions were upregulated and increased of RAI accumulation and its therapeutic effects in ATC. Moreover, K905-0266 TKI increased therapeutic efficacy of RAI in ATC tumour in vivo. In conclusion, we successfully established a novel high-throughput NIS enhancer screening platform to excavate a NIS enhancer and identified K905-0266 TKI among TKI candidates and it's proven to increase the endogenous NIS expression and therapeutic efficacy of RAI in ATC. These findings suggest that a novel highthroughput NIS enhancer screening platform is useful for selecting of NIS promoter enhancers. In addition, K905-0266 TKI can be used to re-induce endogenous NIS expression and recover RAI therapy in ATC.
AB - Radioactive-iodine (RAI) therapy is typically unprevailing as anaplastic thyroid cancer (ATC) management, owing to the decrease in the endogenous sodium iodide symporter (NIS) expression. Therefore, new strategies for NIS re-induction are required to improve the efficacy of RAI therapy in ATC. In this study, we developed a novel high-throughput NIS enhancer screening platform using a dual reporter gene system to identify a potent tyrosine kinase inhibitor (TKI) and selected a new hit compound, K905-0266 TKI. The effects of K905-0266 TKI treatment was validated as RAI accumulation, changes in signalling pathway related to thyroid pathogenesis, and cytotoxicity of RAI depending on re-induction of endogenous NIS expression in ATC. Furthermore, we evaluated enhancement of NIS promoter and therapeutic efficacy of RAI in ATC tumour xenograft mice. After K905-0266 TKI treatment, the expression of endogenous NIS was significantly increased, while phosphorylated- ERK was decreased. In addition, the thyroid-metabolising protein expressions were upregulated and increased of RAI accumulation and its therapeutic effects in ATC. Moreover, K905-0266 TKI increased therapeutic efficacy of RAI in ATC tumour in vivo. In conclusion, we successfully established a novel high-throughput NIS enhancer screening platform to excavate a NIS enhancer and identified K905-0266 TKI among TKI candidates and it's proven to increase the endogenous NIS expression and therapeutic efficacy of RAI in ATC. These findings suggest that a novel highthroughput NIS enhancer screening platform is useful for selecting of NIS promoter enhancers. In addition, K905-0266 TKI can be used to re-induce endogenous NIS expression and recover RAI therapy in ATC.
KW - Anaplastic thyroid cancer
KW - Highthroughput screening
KW - Radioactive-iodine therapy
KW - Sodium iodide symporter
KW - Tyrosine kinase inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85040950360&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.24159
DO - 10.18632/oncotarget.24159
M3 - Article
C2 - 29467951
AN - SCOPUS:85040950360
SN - 1949-2553
VL - 9
SP - 7075
EP - 7087
JO - Oncotarget
JF - Oncotarget
IS - 6
ER -
