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: Dain Son, Yi Rang Na, Eung-Soo Hwang, Seung Hyeok Seok
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 9 Pg. 6225-35 (Feb 28 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24421315 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BAD protein, human
• Enzyme Inhibitors
• Lymphokines
• Platelet-Derived Growth Factor
• bcl-Associated Death Protein
• platelet-derived growth factor C
• Receptor, Platelet-Derived Growth Factor alpha
• Proto-Oncogene Proteins c-akt
• Caspases
• Staurosporine

Topics

• Apoptosis
• Caspases (genetics, metabolism)
• Cell Line, Tumor
• Enzyme Activation (drug effects, genetics)
• Enzyme Inhibitors (pharmacology)
• Female
• Gene Knockdown Techniques
• Humans
• Lymphokines (genetics, metabolism)
• Macrophages (metabolism, pathology)
• Male
• Neoplasms (genetics, metabolism, physiopathology)
• Platelet-Derived Growth Factor (genetics, metabolism)
• Proto-Oncogene Proteins c-akt
• Receptor, Platelet-Derived Growth Factor alpha (genetics, metabolism)
• Signal Transduction
• Staurosporine (pharmacology)
• bcl-Associated Death Protein (genetics, metabolism)