Inhibition of JAK2 signaling by TG101209 enhances radiotherapy in lung cancer models.
Inhibition of JAK2 signaling by TG101209 enhances radiotherapy in lung cancer models.
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DOI：
10.1097/jto.0b013e31820d9d11
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发表时间：
2011-04
期刊：
影响因子：
--
通讯作者：
Lu B
中科院分区：
文献类型：
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作者：
Sun Y;Moretti L;Giacalone NJ;Schleicher S;Speirs CK;Carbone DP;Lu B
持续的 STAT3 激活有助于肺癌的发生。 Survivin 是 STAT3 调节基因之一，具有抗细胞凋亡作用并赋予癌症放射抗性。我们测试了 TG101209（一种 JAK2（一种 STAT3 激活酪氨酸激酶）小分子抑制剂）是否影响生存素表达并使肺癌对辐射敏感。我们研究了用 TG101209 抑制 JAK2 信号传导是否可用于降低存活蛋白表达并增强体外肺癌细胞的放射敏感性和延迟体内肿瘤生长。还探讨了 JAK2 下游信号传导，包括 PI3-K/Akt 和 Ras/MAPK/ERK 通路。 TG101209 抑制 STAT3 激活和生存素表达，并使 HCC2429 (DER=1.34,p=0.002) 和 H460 (DER=1.09,p=0.006) 细胞在克隆形成试验中对辐射敏感。辐射促进了 H460 细胞中的磷酸化 Akt 和磷酸化 ERK，而在 HCC2429 中它们的水平没有变化。用 TG101209 处理后，HCC2429 和 H460 细胞中磷酸 ERK 蛋白水平均降低。与野生型对照细胞相比，转染 K-Ras-12V 突变体的 HCC2429 细胞对辐射和 TG101209 诱导的细胞凋亡具有更强的抵抗力。在体内，与单独放疗相比，在肺异种移植物的放疗中添加TG101209可显着延迟肿瘤生长（>10天），并且耐受性良好。肿瘤切片的免疫组织化学染色显示TG101209增加细胞凋亡并降低细胞增殖和血管密度，表明TG101209还具有抗血管生成作用。 TG101209 在体外和体内增强了放射对肺癌的影响。这项研究表明，根据 K-Ras 突变状态选择肺癌患者对于未来测试 TG101209 与放疗组合的临床试验具有潜在的用途。
Persistent STAT3 activation contributes to lung carcinogenesis. Survivin, one of STAT3-regulated genes, is antiapoptotic and confers cancer radioresistance. We tested whether TG101209, a small-molecule inhibitor of JAK2 (a STAT3-activating tyrosine kinase), affected survivin expression and sensitized lung cancer to radiation. We investigated whether inhibition of JAK2 signaling with TG101209 can be used to reduce survivin expression and enhance radiosensitivity of lung cancer cells in vitro and tumor growth delay in vivo. JAK2 downstream signaling, including PI3-K/Akt and Ras/MAPK/ERK pathways, was also explored. TG101209 inhibited STAT3 activation and survivin expression, and sensitized HCC2429 (DER=1.34,p=0.002) and H460 (DER=1.09,p=0.006) cells to radiation in clonogenic assays. Radiation promoted phospho-Akt and phospho-ERK in H460 cells, while their levels were unchanged in HCC2429. After treatment with TG101209, phospho-ERK protein levels were reduced in both HCC2429 and H460 cells. HCC2429 cells transfected with K-Ras-12V mutant were more resistant to radiation- and TG101209-induced apoptosis than wild-type control cells. In vivo, addition of TG101209 to radiation in lung xenografts produced a significant tumor growth delay (>10 days) compared to radiation alone and was well tolerated. Immunohistochemistry staining of tumor sections showed that TG101209 increased apoptosis and decreased cell proliferation and vascular density, suggesting that TG101209 also has antiangiogenic effects. TG101209 enhanced the effects of radiation in lung cancer in vitro and in vivo. This study suggests the potential utility of selecting lung cancer patients according to K-Ras mutation status for future clinical trials testing combination of TG101209 and radiotherapy.