2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces matrix metalloproteinase (MMP) expression and invasion in A2058 melanoma cells.
There has been a 34% increase in melanoma related mortality in the United States from 1973 to 1992. Although few successful treatments for malignant melanoma exist, it is known that genetic susceptibility and environmental factors contribute to the initiation and progression of melanoma. Excessive UV exposure is considered the main etiological factor in melanoma initiation, however, epidemiological and experimental evidence suggests that exposure to environmental carcinogens contribute to melanoma. We propose that exposure to environmental chemicals that activate the aryl hydrocarbon receptor pathway contribute to melanoma progression, specifically through stimulation of the expression and activity of the matrix metalloproteinases (MMPs). Therefore, we investigated the effect of AhR activation on normal human melanocytes and several melanoma cell lines. The data presented here demonstrate that normal melanocytes and melanoma cells express the AhR and Arnt and are responsive to activation by TCDD. Furthermore, activation of this pathway in transformed melanoma cells (A2058) results in increased expression and activity of MMP-1, MMP-2 and MMP-9, as well as increased invasion using in vitro invasion assays. Furthermore, TCDD-induced expression of the MMP-1 promoter in melanoma cells appears to require different elements than those required in untransformed cells, indicating that this pathway may have multiple mechanisms for activation of MMP expression.
Department of Biochemistry and Microbiology, 76 Lipman Dr., Rutgers, The State University of NJ, New Brunswick, NJ 08901, USA.
C M
CM
Villano
K A
KA
Murphy
A
A
Akintobi
L A
LA
White
D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D004790:Enzyme Induction; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D008544:Melanocytes / Q000187:drug effects* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D012313:RNA; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C497396:ARNT protein, human; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D012313:RNA; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1