Photodynamic therapy mediated induction of early response genes.
Photodynamic therapy (PDT) generates reactive oxygen species which initiate the cytotoxic events of this tumor treatment. We demonstrate that PDT mediated oxidative stress induced a transient increase in the early response genes c-fos, c-jun, c-myc, and egr-1 in murine radiation-induced fibrosarcoma cells. Incubation of exponentially growing cells with porphyrin based photosensitizers in the dark also induced an increase in mRNA levels of early response genes. However, the xanthine photosensitizer, rose bengal, produced increased c-fos mRNA levels only following light treatment. Nuclear runoff experiments confirmed that the induction of c-fos mRNA is controlled in part at the level of transcription. Likewise, a chloramphenicol acetyltransferase reporter construct containing the major c-fos transcriptional response elements was inducible by porphyrin and PDT. Signal transduction pathways associated with PDT mediated c-fos activation were examined by treating cells with protein kinase inhibitors. Staurosporine and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine inhibited PDT mediated c-fos activation while N-(2-guanidinoethyl)-5-isoquinoline-sulfonamide had no effect. In addition, quinacrine, which can inhibit phospholipase activity, blocked PDT induced c-fos mRNA expression. These results suggest that photosensitizer mediated oxidative stress acts through protein kinase-mediated signal transduction pathway(s) to activate early response genes.
Luna
M C
MC
Clayton Ocular Oncology Center, Childrens Hospital Los Angeles, California 90027.
Wong
S
S
Gomer
C J
CJ
D000818:Animals; D004347:Drug Interactions; D005354:Fibrosarcoma / Q000188:drug therapy / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D017781:Genes, Immediate-Early / Q000187:drug effects* / Q000235:genetics*; D016762:Genes, fos / Q000235:genetics; D051379:Mice; D010740:Phospholipases / Q000037:antagonists & inhibitors; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000633:toxicity; D013312:Stress, Physiological / Q000139:chemically induced / Q000503:physiopathology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D017319:Photosensitizing Agents; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D010740:Phospholipases