Induction of autophagy and inhibition of melanoma growth in vitro and in vivo by hyperactivation of oncogenic BRAF.
Induction of autophagy and inhibition of melanoma growth in vitro and in vivo by hyperactivation of oncogenic BRAF.
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DOI：
10.1038/jid.2010.26
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发表时间：
2010-06
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--
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中科院分区：
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在皮肤黑色素瘤中经常发现NRAS和BRAF的激活突变。由于BRAF和RAF同时发生突变的情况极为罕见，因此认为RAS和BRAF的转化是通过共同的机制发生的。此外，有证据表明，NRAS和BRAF癌基因之间的合成致命性关系导致了对具有高活性丝裂原激活蛋白激酶(MAPK)途径的细胞的选择。然而，目前尚不清楚MAPK通路的过度激活是否也能抑制黑色素瘤的发生。在这里，我们展示了在带有致癌BRAF的黑色素瘤细胞(MBRAF)中，高水平的mBRAF诱导ERK过度激活和衰老样表型，并通过抑制雷帕霉素复合体信号的哺乳动物靶点而触发自噬。高水平的mBRAF引起的生长抑制和细胞死亡可以通过下调BRAF蛋白或抑制自噬得到部分挽救，但不能通过抑制MAPK或凋亡途径来缓解。在裸鼠体内，mBRAF过表达肿瘤的生长受到抑制。对人类黑色素瘤和黑色素瘤细胞株的免疫组织化学定量分析显示，BRAF蛋白水平与自噬标记轻链3呈显著正相关。我们的数据提示，致癌的BRAF水平高触发自噬，这可能在黑色素瘤的进展中起作用。
Activating mutations in NRAS and BRAF are found frequently in cutaneous melanomas. Because concurrent mutations of both BRAF and RAS are extremely rare, it is thought that transformation by RAS and BRAF occurs through a common mechanism. Also, there is evidence for a relationship of synthetic lethality between NRAS and BRAF oncogenes that leads to selection against cells with a hyperactive mitogen-activated protein kinase (MAPK) pathway. However, it is not known whether the hyperactivation of the MAPK pathway by overexpression of either oncogene alone could also inhibit melanoma tumorigenesis. Here, we show that in melanoma cells with oncogenic BRAF (mBRAF), high levels of mBRAF induce hyperactivation of ERK and senescence-like phenotype and trigger autophagy by inhibiting the mammalian target of rapamycin complex signaling. Growth inhibition and cell death caused by high mBRAF levels are partially rescued by downregulation of BRAF protein or inhibition of autophagy, but not by inhibition of the MAPK or apoptotic pathways. In nude mice, growth of mBRAF-overexpressing tumors is inhibited. Quantitative immunohistochemical analysis of human melanomas and cell lines showed a significant positive correlation between the levels of BRAF protein and autophagy marker light chain 3. Our data suggest that high oncogenic BRAF levels trigger autophagy, which may have a role in melanoma tumor progression.
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