Nature2014-06-17 4:55 PM

铜在BRAF癌症中所起的一个作用 Copper is required for oncogenic BRAF signaling and tumorigenesis

论文摘要 

很大比例的黑素瘤和一些其他癌症在BRAF 基因中都有突变,其中大部分是在600密码子(codon 600)上,造成MAPK (mitogen-activated protein kinase,即“由有丝分裂原激活的蛋白激酶”)通道的组成性激活(constitutive activation)。在关于铜的运输会通过与激酶MEK结合并激活该激酶来促进果蝇的MAPK信号传导的发现之后,Chris Counter 及同事现在又发现,突变体BRAF的致癌性信号传导需要铜与MEK结合,并促进 ERK1/2的激活,后者是该级联中后面的激酶。通过遗传手段或铜螯合剂来干扰铜的供应,在活体小鼠模型中会减少由BRAF驱动的肿瘤生长,也会减少已变得对BRAF抑制因子有抵抗力的癌细胞的生长。因此,铜螯合剂(在临床中已经用于治疗其他疾病)也许能被证明可用于与BRAF抑制因子相结合来治疗BRAF突变肿瘤,并有可能防止产生抗药性.

Abstract 

The BRAF kinase is mutated, typically Val 600right arrowGlu (V600E), to induce an active oncogenic state in a large fraction of melanomas, thyroid cancers, hairy cell leukaemias and, to a smaller extent, a wide spectrum of other cancers. BRAFV600E phosphorylates and activates the MEK1 and MEK2 kinases, which in turn phosphorylate and activate the ERK1 and ERK2 kinases, stimulating the mitogen-activated protein kinase (MAPK) pathway to promote cancer. Targeting MEK1/2 is proving to be an important therapeutic strategy, given that a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma, an effect that is increased when administered together with a BRAFV600E inhibitor5. We previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu–MEK1 interaction6. Here we show decreasing the levels of CTR1 (Cu transporter 1), or mutations in MEK1 that disrupt Cu binding, decreased BRAFV600E-driven signalling and tumorigenesis in mice and human cell settings. Conversely, a MEK1–MEK5 chimaera that phosphorylated ERK1/2 independently of Cu or an active ERK2 restored the tumour growth of murine cells lacking Ctr1. Cu chelators used in the treatment of Wilson disease decreased tumour growth of human or murine cells transformed by BRAFV600E or engineered to be resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat cancers containing the BRAFV600E mutation.

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