The platelet-derived growth factor receptor alpha is destabilized by geldanamycins in cancer cells.
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.
Matei
Daniela
D
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. dmatei@iupui.edu
Satpathy
Minati
M
Cao
Liyun
L
Lai
Yi-Chun
YC
Nakshatri
Harikrishna
H
Donner
David B
DB
D016475:3T3 Cells; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D000068877:Imatinib Mesylate; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000737:chemistry; D011743:Pyrimidines / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000737:chemistry* / Q000502:physiology; D015398:Signal Transduction
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D001549:Benzamides; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D007976:Leupeptins; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; C112765:tanespimycin; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C001277:geldanamycin