The platelet-derived growth factor receptor alpha is destabilized by geldanamycins in cancer cells.
The platelet-derived growth factor receptor alpha is destabilized by geldanamycins in cancer cells.
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癌细胞中的格尔德霉素会破坏血小板衍生生长因子受体α的稳定性。
DOI：
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发表时间：
2007
影响因子：
4.8
通讯作者：
D. Donner
中科院分区：
文献类型：
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作者：
D. Matei;M. Satpathy;Liyun Cao;Yiyang Lai;H. Nakshatri;D. Donner
热休克蛋白HSP 90作为受体蛋白激酶、类固醇受体和其他细胞内信号分子的伴侣。用安莎霉素抗生素靶向HSP 90会破坏HSP 90复合物客户的正常加工。血小板衍生生长因子受体α（PDGFR α）是一种酪氨酸激酶受体，在几种恶性肿瘤中被上调和激活。在这里，我们发现PDGFR α与HSP 90和辅助分子伴侣cdc 37在卵巢癌、胶质母细胞瘤和肺癌细胞中形成复合物。用HSP 90抑制剂17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）处理表达PDGFR α的癌细胞系促进受体的降解。同样，磷酸化Akt，下游靶标，在用17-AAG处理后降解。相反，在正常人平滑肌细胞或3 T3成纤维细胞中，PDGFR α表达不受17-AAG的影响。蛋白酶体抑制剂MG 132可抑制17-AAG对PDGFR α的降解。在用17-AAG和MG 132处理的细胞中检测到高分子量、泛素化形式的受体。受体的降解也会被PDGFRa的特异性中和抗体抑制，但不会被PDGF的中和抗体或甲磺酸伊马替尼（Gleevec）抑制。最终，PDGFR α介导的细胞增殖被17-AAG抑制。这些结果表明，17-AAG在转化细胞中选择性地促进PDGFR α降解。因此，17-AAG不仅可以靶向突变的酪氨酸激酶，还可以靶向癌细胞中过表达的受体。
The heat shock protein HSP90 serves as a chaperone for receptor protein kinases, steroid receptors, and other intracellular signaling molecules. Targeting HSP90 with ansamycin antibiotics disrupts the normal processing of clients of the HSP90 complex. The platelet-derived growth factor receptor alpha (PDGFRalpha) is a tyrosine kinase receptor up-regulated and activated in several malignancies. Here we show that the PDGFRalpha forms a complex with HSP90 and the co-chaperone cdc37 in ovarian, glioblastoma, and lung cancer cells. Treatment of cancer cell lines expressing the PDGFRalpha with the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) promotes degradation of the receptor. Likewise, phospho-Akt, a downstream target, is degraded after treatment with 17-AAG. In contrast, PDGFRalpha expression is not affected by 17-AAG in normal human smooth muscle cells or 3T3 fibroblasts. PDGFRalpha degradation by 17-AAG is inhibited by the proteasome inhibitor MG132. High molecular weight, ubiquitinated forms of the receptor are detected in cells treated with 17-AAG and MG132. Degradation of the receptor is also inhibited by a specific neutralizing antibody to the PDGFRalpha but not by a neutralizing antibody to PDGF or by imatinib mesylate (Gleevec). Ultimately, PDGFRalpha-mediated cell proliferation is inhibited by 17-AAG. These results show that 17-AAG promotes PDGFRalpha degradation selectively in transformed cells. Thus, not only mutated tyrosine kinases but also overexpressed receptors in cancer cells can be targeted by 17-AAG.