%0 Journal Article %T The important roles of RET, VEGFR2 and the RAF/MEK/ERK pathway in cancer treatment with sorafenib %A Mao Wei-feng %A Shao Min-hua %A Gao Pin-ting %A Ma Ji %A Li Hui-juan %A Li Gai-ling %A Han Bao-hui %A Yuan Chong-gang %J Acta Pharmacologica Sinica %D 2016 %B 2016 %9 %! The important roles of RET, VEGFR2 and the RAF/MEK/ERK pathway in cancer treatment with sorafenib %K %X Aim: To elucidate the roles of receptor tyrosine kinases RET and VEGFR2 and the RAF/MEK/ERK signaling cascade in cancer treatment with sorafenib. Methods: The cell lines A549, HeLa, and HepG2 were tested. The enzyme activity was examined under cell-free conditions using 384-well microplate assays. Cell proliferation was evaluated using the Invitrogen Alarmar Blue assay. Gene expression was analyzed using the Invitrogen SYBR Green expression assays with a sequence detection system. Protein expression analysis was performed using Western blotting. Results: Sorafenib potently suppressed the activities of cRAF, VEGFR2, and RET with IC50 values of 20.9, 4 and 0.4 nmol/L, respectively. Sorafenib inhibited cRAF, VEGFR2, and RET via non-ATP-competitive, ATP-competitive and mixed-type modes, respectively. In contrast, sorafenib exerted only moderate cytotoxic effects on the proliferation of the 3 cell lines. The IC50 values for inhibition of A549, HeLa, and HepG2 cells were 8572, 4163, and 8338 nmol/L, respectively. In the 3 cell lines, sorafenib suppressed the cell proliferation mainly by blocking the MEK/ERK downstream pathway at the posttranscriptional level, which in turn regulated related gene expression via a feed-back mechanism. Conclusion: This study provides novel evidence that protein kinases RET and VEGFR2 play crucial roles in cancer treatment with sorafenib. %U http://www.chinaphar.com/article/view/6782 %V 33 %N 10 %P 1311 %@ 1745-7254