MTOR is activated in the majority of malignant melanomas
MTOR is activated in the majority of malignant melanomas
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DOI：
10.1038/sj.jid.5701074
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发表时间：
2008-04-01
影响因子：
6.5
通讯作者：
Henske, Elizabeth P.
中科院分区：
文献类型：
--
作者：
Karbowniczek, Magdalena;Spittle, Cynthia S.;Henske, Elizabeth P.
本研究的目的是确定雷帕霉素哺乳动物靶点激酶 (mTOR) 的激活是否与人类黑色素瘤相关。我们发现 78/107 例黑色素瘤 (73%) 中核糖体蛋白 S6 存在中度或强度过度磷酸化。相比之下，只有 3/67 良性痣 (4%) 呈中度阳性，没有一个呈强阳性。这些数据表明，与良性黑素细胞病变相比，mTOR 激活与恶性病变密切相关。接下来，我们测试了六种黑色素瘤来源的细胞系，以寻找 mTOR 失调的证据。 6 个品系中的 5 个在血清剥夺 18 小时后显示 S6 持续磷酸化，4 个在氨基酸撤除 30 分钟后出现 S6 磷酸化，表明 mTOR 激活不当。 mTOR 抑制剂雷帕霉素阻断了三种黑色素瘤来源细胞系的增殖，表明 mTOR 激活是黑色素瘤来源细胞的生长促进因子。 mTOR 直接被大脑中富集的小鸟苷三磷酸酶 Ras 同源物 (Rheb) 以法尼基化依赖性方式激活。因此，为了研究 mTOR 激活的机制，我们使用了法尼基转移酶抑制剂 FTI-277，它部分阻断了六种黑色素瘤细胞系中三种的生长。总之，这些数据暗示 mTOR 在黑色素瘤发病机制中的激活，并表明 Rheb 和 mTOR 可能是黑色素瘤治疗的靶点。
The objective of this study was to determine whether activation of the kinase mammalian target of rapamycin ( mTOR) is associated with human melanoma. We found moderate or strong hyperphosphorylation of ribosomal protein S6 in 78/107 melanomas (73%). In contrast, only 3/67 benign nevi (4%) were moderately positive, and none were strongly positive. These data indicate that mTOR activation is very strongly associated with malignant, compared to benign, melanocytic lesions. Next, we tested six melanoma-derived cell lines for evidence of mTOR dysregulation. Five of the six lines showed persistent phosphorylation of S6 after 18 hours of serum deprivation, and four had S6 phosphorylation after 30 minutes of amino-acid withdrawal, indicating inappropriate mTOR activation. The proliferation of three melanoma-derived lines was blocked by the mTOR inhibitor rapamycin, indicating that mTOR activation is a growth-promoting factor in melanoma-derived cells. mTOR is directly activated by the small guanosine triphosphatase Ras homolog enriched in brain ( Rheb), in a farnesylation-dependent manner. Therefore, to investigate the mechanism of mTOR activation, we used the farnesyl transferase inhibitor FTI-277, which partially blocked the growth of three of the six melanoma cell lines. Together, these data implicate activation of mTOR in the pathogenesis of melanoma, and suggest that Rheb and mTOR may be targets for melanoma therapy.