title: Repeated sub-optimal photodynamic treatments with pheophorbide a induce an epithelial mesenchymal transition in prostate cancer cells via nitric oxide.
abstract: Photodynamic therapy (PDT) is a clinically approved treatment that causes a selective cytotoxic effect in cancer cells. In addition to the production of singlet oxygen and reactive oxygen species, PDT can induce the release of nitric oxide (NO) by up-regulating nitric oxide synthases (NOS). Since non-optimal PDT often causes tumor recurrence, understanding the molecular pathways involved in the photoprocess is a challenging task for scientists. The present study has examined the response of the PC3 human metastatic prostate cancer cell line following repeated low-dose pheophorbide a treatments, mimicking non-optimal PDT treatment. The analysis was focused on the NF-kB/YY1/RKIP circuitry as it is (i) dysregulated in cancer cells, (ii) modulated by NO and (iii) correlated with the epithelial to mesenchymal transition (EMT). We hypothesized that a repeated treatment of non-optimal PDT induces low levels of NO that lead to cell growth and EMT via the regulation of the above circuitry. The expressions of gene products involved in the circuitry and in EMT were analyzed by western blot. The findings demonstrate the cytoprotective role of NO following non-optimal PDT treatments that was corroborated by the use of L-NAME, an inhibitor of NOS.
authors.affiliation: Department of Medical and Biological Sciences, School of Medicine, University of Udine, Udine, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Della Pietra
authors.affiliation: Department of Medical and Biological Sciences, School of Medicine, University of Udine, Udine, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Simonella
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bonavida
authors.affiliation: Department of Medical and Biological Sciences, School of Medicine, University of Udine, Udine, Italy.
authors.forename: Luigi Emilio
authors.initials: LE
authors.lastname: Xodo
authors.affiliation: Department of Medical and Biological Sciences, School of Medicine, University of Udine, Udine, Italy. Electronic address: valentina.rapozzi@uniud.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Rapozzi
mesh_terms: D045744:Cell Line, Tumor; D002734:Chlorophyll / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000528:radiation effects*; D006801:Humans; D008297:Male; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010778:Photochemotherapy / Q000009:adverse effects*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D011838:Radiation-Sensitizing Agents; D002734:Chlorophyll; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C032623:pheophorbide a
keywords: Epithelial–mesenchymal transition; Nitric oxide; Pheophorbide a; Photodynamic therapy; Prostate cancer cells