Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy
Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy
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DOI：
10.1093/emboj/21.10.2407
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发表时间：
2002-05-15
期刊：
影响因子：
11.4
通讯作者：
Yarden, Y
中科院分区：
文献类型：
--
作者：
Citri, A;Alroy, I;Yarden, Y
ErbB-2/HER 2的过表达与侵袭性人类恶性肿瘤相关，靶向癌蛋白的治疗策略目前处于临床应用的不同阶段。阻断激酶的核苷酸结合位点的酪氨酸激酶抑制剂（TKI）对肿瘤特别有效。在这里，我们报告了TKI的一种意想不到的活性：沿着酪氨酸磷酸化的抑制，它们增强了泛素化，加速了ErbB-2分子的内吞作用和随后的细胞内破坏。特别有效的是不可逆的TKI（CI-1033），其烷基化对ErbB受体特异性的半胱氨酸。TKI刺激的降解途径似乎是分子伴侣介导的，并且与热休克蛋白90（Hsp 90）拮抗剂格尔德霉素和应激诱导机制相同。与该结论一致，CI-1033和格尔德霉素相加抑制肿瘤细胞生长。基于药物诱导的ErbB-2降解模型，我们提出了一种通过靶向与分子伴侣相互作用来选择性破坏癌蛋白的一般策略。
Overexpression of ErbB-2/HER2 is associated with aggressive human malignancies, and therapeutic strategies targeting the oncoprotein are currently in different stages of clinical application. Tyrosine kinase inhibitors (TKIs) that block the nucleotide-binding site of the kinase are especially effective against tumors. Here we report an unexpected activity of TKIs: along with inhibition of tyrosine phosphorylation, they enhance ubiquitylation and accelerate endocytosis and subsequent intracellular destruction of ErbB-2 molecules. Especially potent is an irreversible TKI (CI-1033) that alkylates a cysteine specific to ErbB receptors. The degradative pathway stimulated by TKIs appears to be chaperone mediated, and is common to the heat shock protein 90 (Hsp90) antagonist geldanamycin and a stress-induced mechanism. In agreement with this conclusion, CI-1033 and geldanamycin additively inhibit tumor cell growth. Based upon a model for drug-induced degradation of ErbB-2, we propose a general strategy for selective destruction of oncoproteins by targeting their interaction with molecular chaperones.