Src inhibitors in suppression of papillary thyroid carcinoma growth.
Src inhibitors in suppression of papillary thyroid carcinoma growth.
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DOI：
10.1002/hed.23316
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发表时间：
2014-03
影响因子：
2.9
通讯作者：
Clayman, Gary L.
中科院分区：
文献类型：
--
作者：
Henderson, Ying C.;Toro-Serra, Rafael;Chen, Yunyun;Ryu, Junsun;Frederick, Mitchell J.;Zhou, Ge;Gallick, Gary E.;Lai, Stephen Y.;Clayman, Gary L.
甲状腺乳头状癌是最常见的甲状腺恶性肿瘤。大多数乳头状甲状腺癌含有BRAF突变或RET/PTC重排，从而为生物治疗提供了靶点。我们以前的研究表明，甲状腺乳头状癌与BRAF突变和RET/PTC 1重排有不同的敏感性MEK 1/2抑制剂，这表明不同的信号转导途径参与。用Src抑制剂PP 2、SU 6656或达沙替尼（dasatinib）和si-Src RNA，通过Western blot分析和增殖分析检测甲状腺乳头状癌细胞中Src信号转导通路。原位异种移植小鼠模型用于使用达沙替尼的体内研究。在甲状腺乳头状癌细胞中，Src抑制剂抑制p-Src和p-FAK，并抑制细胞生长。此外，与MEK抑制剂（CI-1040）组合，在RET/PTC 1重排细胞中检测到p-ERK 1/2去磷酸化的显著抑制和延长。Src家族激酶/ABL抑制剂达沙替尼显著降低了接种携带RET/PTC 1重排的乳头状甲状腺癌细胞的小鼠的肿瘤体积。在BRAF突变的甲状腺乳头状癌细胞中，Src抑制剂有效抑制p-Src表达，达沙替尼每日两次治疗可显著降低肿瘤体积。Src抑制剂在体外有效抑制甲状腺乳头状癌细胞中Src信号转导通路，达沙替尼在体内抑制肿瘤生长。上述结果提示Src信号转导通路在甲状腺乳头状癌细胞的生长调控中起重要作用。Src和MEK 1/2抑制剂的组合延长了携带RET/PTC 1重排的甲状腺乳头状癌中ERK 1/2的去磷酸化，这表明可能需要与其他信号转导途径的互补抑制剂的组合治疗来有效抑制这些细胞的生长并诱导凋亡。
Papillary thyroid carcinoma is the most common thyroid malignancy. Most papillary thyroid carcinomas contain BRAF mutations or RET/PTC rearrangements, thus providing targets for biologic therapy. Our previous studies had suggested papillary thyroid carcinomas with a BRAF mutation and the RET/PTC1 rearrangement have different sensitivities to MEK1/2 inhibitors, suggesting different signaling transduction pathways were involved. Src signaling transduction pathway in papillary thyroid carcinoma cells was examined using Src inhibitors (PP2, SU6656, or dasatinib) and si-Src RNA in vitro by Western blot analysis and proliferation analysis. An orthotopic xenograft mouse model was used for the in vivo studies using dasatinib. In papillary thyroid carcinoma cells, Src inhibitors suppressed p-Src and p-FAK and inhibited cell growth. In addition, significant suppression and extension of the p-ERK1/2 dephosphorylation were detected in RET/PTC1-rearranged cells in combination with a MEK inhibitor (CI-1040). The Src family kinase/ABL inhibitor, dasatinib, significantly decreased tumor volume in mice inoculated with papillary thyroid carcinoma cells carrying the RET/PTC1 rearrangement. In BRAF-mutated papillary thyroid carcinoma cells, Src inhibitors effectively suppressed p-Src expression and dasatinib significantly decreased tumor volume with twice daily treatment. Src inhibitors effectively inhibited the Src signaling transduction pathway in papillary thyroid carcinoma cells in vitroand dasatinib suppressed tumor growth in vivo. These results suggested that Src signaling transduction pathway plays an important role in regulating growth in papillary thyroid carcinoma cells. Combination of Src and MEK1/2 inhibitors extended the dephosphorylation of ERK1/2 in papillary thyroid carcinomas carrying the RET/PTC1 rearrangement suggesting that combination therapy with complementary inhibitors of other signaling transduction pathways may be needed to effectively suppress growth and induce apoptosis in these cells.
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影响因子：
--
作者：
Ahn, Soon-Hyun;Henderson, Ying;Clayman, Gary L.
通讯作者：
Clayman, Gary L.
DOI：
10.1158/1078-0432.ccr-11-2892
发表时间：
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期刊：
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影响因子：
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