Ionizing radiation synergistic induction of cyclooxygenase-2 with benzo[a]pyrene diol-epoxide through nuclear factor of activated T cells in mouse epidermal Cl 41 cells.
Carcinogenic effects of ionizing radiation and benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), a major metabolite of benzo[a]pyrene (B[a]P), have been well demonstrated both in vitro and in vivo. Two-stage carcinogenesis results indicate that mouse skin is highly susceptible to both ionizing radiation and benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), a major metabolite of benzo[a]pyrene (B[a]P). It is believed that signaling pathways leading to the regulation of gene expression play a significant role in the development of skin cancers. The NFAT family of proteins are important transcription factors involved in the regulation of various target genes, such as IL-1 and TNF-alpha, which play key roles in the regulation of inflammation and carcinogenesis. Thus, the effect of ionizing radiation and B[a]PDE on COX-2 induction and NFAT3 activation, and their relationship, was investigated in mouse epidermal Cl 41 cells. We found that B[a]PDE exposure induced a very high level of NFAT activation in mouse epidermal Cl 41 cells. Ionizing radiation exhibited a synergistic effect with B[a]PDE on NFAT activation and COX-2 induction, while ionizing radiation alone had no effect. By stably knocking down NFAT3 protein expression by means of the specific interfering RNA (siRNA) technique, we found that COX-2 induction by B[a]PDE and the synergistic effect of ionizing radiation with B[a]PDE was totally blocked. These results indicate that ionizing radiation acts synergistically with B[a]PDE on COX-2 induction, and the synergism is dependent on the NFAT3 pathway.
Zhang
Ronghe
R
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
Li
Jingxia
J
Burns
Fredric J
FJ
Huang
Chuanshu
C
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects / Q000528:radiation effects; D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014965:X-Rays
D002273:Carcinogens; D050778:NFATC Transcription Factors; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D008156:Luciferases; D051546:Cyclooxygenase 2