title: Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells.
abstract: Photodynamic therapy (PDT) is an anticancer approach utilizing a light-absorbing molecule and visible light irradiation to generate, in the presence of O(2), cytotoxic reactive oxygen species, which cause tumor ablation. Given that the photosensitizer hypericin is under consideration for PDT treatment of bladder cancer we used oligonucleotide microarrays in the T24 bladder cancer cell line to identify differentially expressed genes with therapeutic potential. This study reveals that the expression of several genes involved in various metabolic processes, stress-induced cell death, autophagy, proliferation, inflammation and carcinogenesis is strongly affected by PDT and pinpoints the coordinated induction of a cluster of genes involved in the unfolded protein response pathway after endoplasmic reticulum stress and in antioxidant response. Analysis of PDT-treated cells after p38(MAPK) inhibition or silencing unraveled that the induction of an important subset of differentially expressed genes regulating growth and invasion, as well as adaptive mechanisms against oxidative stress, is governed by this stress-activated kinase. Moreover, p38(MAPK) inhibition blocked autonomous regrowth and migration of cancer cells escaping PDT-induced cell death. This analysis identifies new molecular effectors of the cancer cell response to PDT opening attractive avenues to improve the therapeutic efficacy of hypericin-based PDT of bladder cancer.
authors.affiliation: Department Molecular and Cell Biology, Faculty of Medicine, Catholic University of Leuven, Brabant, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Buytaert
authors.forename: J Y
authors.initials: JY
authors.lastname: Matroule
authors.forename: S
authors.initials: S
authors.lastname: Durinck
authors.forename: P
authors.initials: P
authors.lastname: Close
authors.forename: S
authors.initials: S
authors.lastname: Kocanova
authors.forename: J R
authors.initials: JR
authors.lastname: Vandenheede
authors.forename: P A
authors.initials: PA
authors.lastname: de Witte
authors.forename: J
authors.initials: J
authors.lastname: Piette
authors.forename: P
authors.initials: P
authors.lastname: Agostinis
mesh_terms: D000873:Anthracenes; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D010569:Perylene / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000873:Anthracenes; D014408:Biomarkers, Tumor; D017319:Photosensitizing Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D010569:Perylene; C004965:hypericin; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases