title: Platelet-derived growth factor-C (PDGF-C) induces anti-apoptotic effects on macrophages through Akt and Bad phosphorylation.
abstract: PDGF-C, which is abundant in the malignant breast tumor microenvironment, plays an important role in cell growth and survival. Because tumor-associated macrophages (TAMs) contribute to cancer malignancy, macrophage survival mechanisms are an attractive area of research into controlling tumor progression. In this study, we investigated PDGF-C-mediated signaling pathways involved in anti-apoptotic effects in macrophages. We found that the human malignant breast cancer cell line MDA-MB-231 produced high quantities of PDGF-C, whereas benign MCF-7 cells did not. Recombinant PDGF-C induced PDGF receptor α chain phosphorylation, followed by Akt and Bad phosphorylation in THP-1-derived macrophages. MDA-MB-231 culture supernatants also activated macrophage PDGF-Rα. PDGF-C prevented staurosporine-induced macrophage apoptosis by inhibiting the activation of caspase-3, -7, -8, and -9 and cleavage of poly(ADP-ribose) polymerase. Finally, TAMs isolated from the PDGF-C knockdown murine breast cancer cell line 4T1 and PDGF-C knockdown MDA-MB-231-derived tumor mass showed higher rates of apoptosis than the respective WT controls. Collectively, our results suggest that tumor cell-derived PDGF-C enhances TAM survival, promoting tumor malignancy.
authors.affiliation: From the Department of Microbiology and Immunology, and Institute of Endemic Disease, College of Medicine, Seoul National University, Seoul 110-799, Korea.
authors.forename: Dain
authors.initials: D
authors.lastname: Son
authors.forename: Yi Rang
authors.initials: YR
authors.lastname: Na
authors.forename: Eung-Soo
authors.initials: ES
authors.lastname: Hwang
authors.forename: Seung Hyeok
authors.initials: SH
authors.lastname: Seok
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494819:BAD protein, human; D004791:Enzyme Inhibitors; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D051025:bcl-Associated Death Protein; C411423:platelet-derived growth factor C; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D019311:Staurosporine
keywords: Akt; Apoptosis; Bad; Breast Cancer; Caspase; Macrophages; PI 3-kinase (PI3K); Platelet-derived Growth Factor-C (PDGF-C)