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

Academic Article

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 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.
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    Keywords

  • 3T3 Cells, Animals, Antibiotics, Antineoplastic, Antineoplastic Agents, Benzamides, Benzoquinones, Cell Line, Tumor, Cell Proliferation, Humans, Imatinib Mesylate, Lactams, Macrocyclic, Leupeptins, Mice, Piperazines, Platelet-Derived Growth Factor, Pyrimidines, Receptor, Platelet-Derived Growth Factor alpha, Signal Transduction
  • Digital Object Identifier (doi)

    Author List

  • Matei D; Satpathy M; Cao L; Lai Y-C; Nakshatri H; Donner DB
  • Start Page

  • 445
  • End Page

  • 453
  • Volume

  • 282
  • Issue

  • 1