The platelet-derived growth factor receptor α is destabilized by geldanamycins in cancer cells

Daniela Matei, Minati Satpathy, Liyun Cao, Yi Chun Lai, Harikrishna Nakshatri, David B. Donner

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54 Scopus citations

Abstract

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 α (PDGFRα) is a tyrosine kinase receptor up-regulated and activated in several malignancies. Here we show that the PDGFRα forms a complex with HSP90 and the co-chaperone cdc37 in ovarian, glioblastoma, and lung cancer cells. Treatment of cancer cell lines expressing the PDGFRα with the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) promotes degradationofthereceptor.Likewise,phospho-Akt, a downstream target, is degraded after treatment with 17-AAG. In contrast, PDGFRα expression is not affected by 17-AAG in normal human smooth muscle cells or 3T3 fibroblasts. PDGFRα 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 PDGFRα but not by a neutralizing antibody to PDGF or by imatinib mesylate (Gleevec). Ultimately, PDGFRα-mediated cell proliferation is inhibited by 17-AAG. These results show that 17-AAG promotes PDGFRα degradation selectively in transformed cells. Thus, not only mutated tyrosine kinases but also overexpressed receptors in cancer cells can be targeted by 17-AAG.

Original languageEnglish (US)
Pages (from-to)445-453
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number1
DOIs
StatePublished - Jan 5 2007

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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