Author:

Keywords:

photodynamic therapy, microarrays, p38(mapk), endoplasmic-reticulum stress, activated protein-kinase, p38 map kinase, messenger-rna stabilization, signaling pathways, er stress, induced apoptosis, oxidative stress, epithelial-cells, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Oncology, Cell Biology, Genetics & Heredity, p38(MAPK), ACTIVATED PROTEIN-KINASE, PHOTODYNAMIC THERAPY, P38 MAPK, SIGNALING PATHWAYS, UP-REGULATION, ER STRESS, EXPRESSION, GENE, TRANSCRIPTION, INHIBITION, Anthracenes, Apoptosis, Biomarkers, Tumor, Cell Death, Cell Line, Tumor, Cell Movement, Cell Proliferation, Gene Expression Profiling, Humans, Oligonucleotide Array Sequence Analysis, Oxidative Stress, Perylene, Photochemotherapy, Photosensitizing Agents, Protein Kinase C, RNA, Messenger, RNA, Small Interfering, Radiation-Sensitizing Agents, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Urinary Bladder Neoplasms, p38 Mitogen-Activated Protein Kinases, 1103 Clinical Sciences, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3101 Biochemistry and cell biology, 3211 Oncology and carcinogenesis

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.