[PDGFR alpha is destabilized by geldanamycins in cancer cells]
>> J Biol Chem. 2006 Nov 1; [Epub ahead of print]
The platelet derived growth factor receptor alpha is destabilized by geldanamycins in cancer cells.
Matei D, Satpathy M, Cao L, Lai YC, Nakshatri H, Donner DB.
Indiana University, Indianapolis, IN 46202.
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 PDGFRa is a tyrosine kinase receptor upregulated and activated in several malignancies. Here we show that the PDGFRa forms a complex with HSP90 and the co-chaperone cdc37 in ovarian, glioblastoma and lung cancer cells. Treatment of cancer cell lines expressing the PDGFRa 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, PDGFRa expression is not affected by 17-AAG in normal human smooth muscle cells (HSMC) or 3T3 fibroblasts. PDGFRa 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 PDGFRa, but not by a neutralizing antibody to PDGF or by Gleevec. Ultimately, PDGFRa mediated cell proliferation is inhibited by 17-AAG. These results show that 17-AAG promotes PDGFRa degradation selectively in transformed cells. Thus, not only mutated tyrosine kinases, but also overexpressed receptors in cancer cells can be targeted by 17-AAG.<<
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