title: PPAR-gamma activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer.
abstract: Activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) results in inhibition of tumor growth in various types of cancers, but the mechanism(s) by which PPAR-gamma induces growth arrest has not been completely defined. In a recent study, we demonstrate that treatment of A549 (human non small cell lung cancer cell line) tumor-bearing SCID mice with PPAR-gamma ligands troglitazone (Tro) and pioglitazone significantly inhibits primary tumor growth. In this study, immunohistochemical analysis of Tro-treated and Pio-treated tumors with factor VIII antibody revealed a significant reduction in blood vessel density compared to tumors in control animals, suggesting inhibition of angiogenesis. Further analysis showed that treatment of A549 cells in vitro with Tro or transient transfection of A549 cells with constitutively active PPAR-gamma (VP16-PPAR-gamma) construct blocked the production of the angiogenic ELR+CXC chemokines IL-8 (CXCL8), ENA-78 (CXCL5), and Gro-alpha (CXCL1). Similarly, an inhibitor of NF-kappa B activation (PDTC) also blocked CXCL8, CXCL5, and CXCL1 production, consistent with their NF-kappa B-dependent regulation. Conditioned media from A549 cells induce human microvascular endothelial cell (HMVEC) chemotaxis. However, conditioned media from Tro-treated A549 cells induced significantly less HMVEC chemotaxis compared to untreated A549 cells. Furthermore, PPAR-gamma activation inhibited NF-kappa B transcriptional activity, as assessed by TransAM reporter gene assay. Collectively, our data suggest that PPAR-gamma ligands can inhibit tumor-associated angiogenesis by blocking the production of ELR+CXC chemokines, which is mediated through antagonizing NF-kappaB activation. These antiangiogenic effects likely contribute to the inhibition of primary tumor growth by PPAR-gamma ligands.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Venkateshwar G
authors.initials: VG
authors.lastname: Keshamouni
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Arenberg
authors.forename: Raju C
authors.initials: RC
authors.lastname: Reddy
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Newstead
authors.forename: Shalini
authors.initials: S
authors.lastname: Anthwal
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D054360:Chemokine CXCL1; D054371:Chemokine CXCL11; D054365:Chemokine CXCL5; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology; D002633:Chemotaxis; D002839:Chromans / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D005169:Factor VIII / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D008833:Microcirculation; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014162:Transfection; D000077288:Troglitazone
chemical_list: C475829:CXCL1 protein, human; C515202:CXCL11 protein, human; C486263:CXCL5 protein, human; D054360:Chemokine CXCL1; D054371:Chemokine CXCL11; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; D002839:Chromans; D017077:Culture Media, Conditioned; C515203:Cxcl11 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D008024:Ligands; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D005169:Factor VIII; D011392:Proline; D000077288:Troglitazone; D000077205:Pioglitazone