Activation of the platelet-derived growth factor-receptor enhances survival of murine bone endothelial cells.
The activation of the microvascular endothelial cell platelet-derived growth factor (PDGF) receptor (PDGF-R) by PDGF has been implicated in neoplastic angiogenesis. Here, we established cultures of murine bone microvascular endothelial cells and examined their response to stimulation with PDGF BB ligand and to blockade of PDGF-R signaling with the tyrosine kinase inhibitor STI571 (Gleevec). The addition of STI571 to cultures of bone endothelial cells blocked PDGF BB-induced phosphorylation in a dose-dependent manner and completely abrogated the activation of downstream targets Akt and ERK1/2. Coadministration of STI571 and Taxol also induced the activation of procaspase-3 and significant apoptosis. These data suggest that phosphorylation of PDGF-R stimulates survival pathways in bone endothelial cells and that by selectively inhibiting PDGF-R signaling with STI571, the cells are rendered sensitive to Taxol treatment. The therapeutic combination of STI571 and Taxol may be a powerful tool for targeting tumor-associated endothelial cells in the skeletal compartment.
Langley
Robert R
RR
Department of Cancer Biology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
Fan
Dominic
D
Tsan
Rachel Z
RZ
Rebhun
Robert
R
He
Junqin
J
Kim
Sun-Jin
SJ
Fidler
Isaiah J
IJ
D000818:Animals; D000077214:Becaplermin; D001549:Benzamides; D001842:Bone and Bones / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta; D017239:Paclitaxel