Nuclear MET requires ARF and is inhibited by carbon nanodots through binding to phospho-tyrosine in prostate cancer
Nuclear MET requires ARF and is inhibited by carbon nanodots through binding to phospho-tyrosine in prostate cancer
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DOI：
10.1038/s41388-018-0608-2
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发表时间：
2019-04-18
期刊：
影响因子：
8
通讯作者：
Benassi, Enrico
中科院分区：
文献类型：
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作者：
Xie, Yingqiu;Fan, Haiyan;Benassi, Enrico
核受体酪氨酸激酶(NRTK)在许多类型的癌症中异常上调，但nRTK的调控仍不清楚。我们以前发现雄激素剥夺疗法(ADT)在去势抵抗前列腺癌(CRPC)标本中诱导nMET。通过基因表达谱芯片再分析，我们确定在Pten/Trp53条件性基因敲除小鼠模型中，nMET信号需要ARF才能促进CRPC的生长。因此，在人类前列腺癌(PCa)标本中，MET/nMET异常升高与ARF相关。从机制上讲，ARF通过与MET胞浆结构域结合而使nMET升高，从而稳定MET。此外，碳纳米点通过DNA损伤反应使癌细胞对MET抑制剂重新敏感。通过计算和实验验证了碳纳米点对磷酸化的抑制作用是通过与磷酸酪氨酸的磷酸基团结合来实现的。因此，nMET对于MET抑制剂的精确治疗至关重要。我们的发现首次表明，通过碳纳米点靶向nMET轴可以成为克服癌症尤其是前列腺癌耐药的一种新途径。
Nuclear receptor tyrosine kinases (nRTKs) are aberrantly upregulated in many types of cancers, but the regulation of nRTK remains unclear. We previously showed androgen deprivation therapy (ADT) induces nMET in castration-resistant prostate cancer (CRPC) specimens. Through gene expression microarray profiles reanalysis, we identified that nMET signaling requires ARF for CRPC growth in Pten/Trp53 conditional knockout mouse model. Accordingly, aberrant MET/nMET elevation correlates with ARF in human prostate cancer (PCa) specimens. Mechanistically, ARF elevates nMET through binding to MET cytoplasmic domain to stabilize MET. Furthermore, carbon nanodots resensitize cancer cells to MET inhibitors through DNA damage response. The inhibition of phosphorylation by carbon nanodots was identified through binding to phosphate group of phospho-tyrosine via computational calculation and experimental assay. Thus, nMET is essential to precision therapy of MET inhibitor. Our findings reveal for the first time that targeting nMET axis by carbon nanodots can be a novel avenue for overcoming drug resistance in cancers especially prostate cancer.