Human bone marrow activates the Akt pathway in metastatic prostate cells through transactivation of the alpha-platelet-derived growth factor receptor.
The factors regulating the bone tropism of disseminated prostate cancer cells are still vaguely defined. We report that prostate cancer cells that metastasize to the skeleton respond to human bone marrow with a robust stimulation of the phosphatidylinositol 3-kinase/Akt pathway, whereas prostate cells that lack bone-metastatic potential respond negligibly. The majority of this Akt activation is dependent on alpha-platelet-derived growth factor receptor (alpha-PDGFR) signaling, which was shown using the small-molecule inhibitor of PDGFR signaling AG1296. Low concentrations of PDGF-AA and PDGF-BB found in bone marrow aspirates, which were detected by ELISA, do not account for the high levels of alpha-PDGFR signaling. Additionally, neutralizing PDGF binding using a alpha-PDGFR-specific antibody (IMC-3G3) failed to produce a significant inhibition of bone marrow-induced Akt activation. However, the inhibitory effect of IMC-3G3 rivaled that of AG1296 when incubation was done under conditions that stimulated alpha-PDGFR internalization. We conclude that alpha-PDGFR is activated by multiple soluble factors contained within human bone marrow, in addition to its natural ligands, and this transactivation is dependent on receptor localization to the plasma membrane. Therefore, alpha-PDGFR expression may provide select prostate phenotypes with a growth advantage within the bone microenvironment.
Dolloff
Nathan G
NG
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA.
Russell
Mike R
MR
Loizos
Nick
N
Fatatis
Alessandro
A
D000293:Adolescent; D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000918:Antibody Specificity; D000077214:Becaplermin; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D001859:Bone Neoplasms / Q000556:secondary; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020574:Proto-Oncogene Proteins c-sis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D020032:Tyrphostins / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D020032:Tyrphostins; C075278:platelet-derived growth factor A; C106250:6,7-dimethoxy-3-phenylquinoxaline; D000077214:Becaplermin; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051058:Oncogene Protein v-akt