Heparin affin regulatory peptide/pleiotrophin mediates fibroblast growth factor 2 stimulatory effects on human prostate cancer cells.
Fibroblast growth factor 2 (FGF2) is a pleiotropic growth factor that has been implicated in prostate cancer formation and progression. In the present study we found that exogenous FGF2 significantly increased human prostate cancer LNCaP cell proliferation and migration. Heparin affin regulatory peptide (HARP) or pleiotrophin seems to be an important mediator of FGF2 stimulatory effects, since the latter had no effect on stably transfected LNCaP cells that did not express HARP. Moreover, FGF2, through FGF receptors (FGFRs), significantly induced HARP expression and secretion by LNCaP cells and increased luciferase activity of a reporter gene vector carrying the full-length promoter of HARP gene. Using a combination of Western blot analyses, as well as genetic and pharmacological inhibitors, we found that activation of FGFR by FGF2 in LNCaP cells leads to NAD(P)H oxidase-dependent hydrogen peroxide production, phosphorylation of ERK1/2 and p38, activation of AP-1, increased expression and secretion of HARP, and, finally, increased cell proliferation and migration. These results establish the role and the mode of activity of FGF2 in LNCaP cells and support an interventional role of HARP in FGF2 effects, providing new insights on the interplay among growth factor pathways within prostate cancer cells.
Hatziapostolou
Maria
M
Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, GR 26504 Patras, Greece.
Polytarchou
Christos
C
Katsoris
Panagiotis
P
Courty
Jose
J
Papadimitriou
Evangelia
E
D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D016207:Cytokines / Q000235:genetics* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D017930:Genes, Reporter; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007155:Immunologic Factors / Q000627:therapeutic use*; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D016877:Oxidants / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000378:metabolism
D002352:Carrier Proteins; D016207:Cytokines; D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D016877:Oxidants; D011758:Pyrroles; D012333:RNA, Messenger; D011994:Recombinant Proteins; C105686:SU 5402; D016222:Fibroblast Growth Factor 2; C066845:pleiotrophin; D006861:Hydrogen Peroxide; D008156:Luciferases