title: Platelet-activating factor induces cell cycle arrest and disrupts the DNA damage response in mast cells.
abstract: Platelet-activating factor (PAF) is a potent phospholipid modulator of inflammation that has diverse physiological and pathological functions. Previously, we demonstrated that PAF has an essential role in ultraviolet (UV)-induced immunosuppression and reduces the repair of damaged DNA, suggesting that UV-induced PAF is contributing to skin cancer initiation by inducing immune suppression and also affecting a proper DNA damage response. The exact role of PAF in modulating cell proliferation, differentiation or transformation is unclear. Here, we investigated the mechanism(s) by which PAF affects the cell cycle and impairs early DNA damage response. PAF arrests proliferation in transformed and nontransformed human mast cells by reducing the expression of cyclin-B1 and promoting the expression of p21. PAF-treated cells show a dose-dependent cell cycle arrest mainly at G2-M, and a decrease in the DNA damage response elements MCPH1/BRIT-1 and ataxia telangiectasia and rad related (ATR). In addition, PAF disrupts the localization of p-ataxia telangiectasia mutated (p-ATM), and phosphorylated-ataxia telangiectasia and rad related (p-ATR) at the site of DNA damage. Whereas the potent effect on cell cycle arrest may imply a tumor suppressor activity for PAF, the impairment of proper DNA damage response might implicate PAF as a tumor promoter. The outcome of these diverse effects may be dependent on specific cues in the microenvironment.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Puebla-Osorio
authors.affiliation: Dipartimento Scienze della Vita e dell'Ambiente, Universita Politecnica delle Marche, Ancona, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Damiani
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Bover
authors.affiliation: 1] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] The University of Texas, Graduate School for Biomedical Sciences, Houston, TX, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Ullrich
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004249:DNA Damage / Q000187:drug effects*; D006801:Humans; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D010972:Platelet Activating Factor / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D010972:Platelet Activating Factor