title: PEDF inhibits IL8 production in prostate cancer cells through PEDF receptor/phospholipase A2 and regulation of NFκB and PPARγ.
abstract: Interleukin-8 (IL8/CXCL8) has been described as a key effector in prostate cancer progression and resistance to standard chemotherapeutic drugs. In the present study, we investigated the effect of the natural, angio-inhibitory and anti-tumoral Pigment Epithelium-Derived Factor (PEDF) on the expression of IL8 cytokine by prostate cancer cells. Using a cytokine antibody array and ELISA, in addition to IL8 quantitative RT PCR, we showed that PEDF inhibits the production of IL8 in human hormone-refractory prostate cancer cells, and delays the growth of these cells in vitro. IL8 reduction was mimicked in cancer cells treated with PPARγ agonist and NFκB-specific inhibitors. Accordingly, PPARγ expression increased in response to PEDF, whereas RelA/p65 expression and nuclear localization, and NFκB transcriptional activity decreased. NFκB deactivation was reversed by the PPARγ antagonist GW9662 and PPARγ (Leu(468)/Glu(471)) dominant negative suggesting a PPARγ-dependent process. We also investigated PEDF Receptor/PLA2 as key player in this pathway by small interference RNA. PEDFR knock down in prostate cancer cells reversed PEDF-induced PPARγ up-regulation, and NFκB and IL8 inhibition compared to non-targeting control siRNA. We conclude that by binding to PEDFR, PEDF up-regulates PPARγ, leading subsequently to suppressed NFκB-mediated transcriptional activation, reduced production of IL8 and limited proliferation of prostate cancer cells. These results reinforce PEDF's therapeutic potential and imply that blocking IL8 could represent a novel alternative for prostate cancer treatment.
authors.affiliation: Department of Urology, Texas Tech University-Health Sciences Center, Lubbock, TX 79430, USA. Jennifer.marable@ttuhsc.edu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hirsch
authors.forename: Christina Lisa
authors.initials: CL
authors.lastname: Johnson
authors.forename: Thomas
authors.initials: T
authors.lastname: Nelius
authors.forename: Ronald
authors.initials: R
authors.lastname: Kennedy
authors.forename: Werner de
authors.initials: Wd
authors.lastname: Riese
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Filleur
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000737:chemistry; D005136:Eye Proteins / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism*; D015843:Serpins / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D017077:Culture Media, Conditioned; D005136:Eye Proteins; D016209:Interleukin-8; D016328:NF-kappa B; D009414:Nerve Growth Factors; D047495:PPAR gamma; D054467:Phospholipases A2; D018013:Receptors, Neuropeptide; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C400531:pigment epithelium-derived factor receptor