Cyclooxygenase-2 induction by arsenite is through a nuclear factor of activated T-cell-dependent pathway and plays an antiapoptotic role in Beas-2B cells.
Arsenite is a well known metalloid human carcinogen, and epidemiological evidence has demonstrated its association with the increased incidence of lung cancer. However, the mechanism involved in its lung carcinogenic effect remains obscure. The current study demonstrated that exposure of human bronchial epithelial cells (Beas-2B) to arsenite resulted in a marked induction of cyclooxygenase (COX)-2, an important mediator for inflammation and tumor promotion. Exposure of the Beas-2B cells to arsenite also led to significant transactivation of nuclear factor of activated T-cells (NFAT), but not activator protein-1 (AP-1) and NFkappaB, suggesting that NFAT, rather than AP-1 or NFkappaB, is implicated in the responses of Beas-2B cells to arsenite exposure. Furthermore, we found that inhibition of the NFAT pathway by either chemical inhibitors, dominant negative mutants of NFAT, or NFAT3 small interference RNA resulted in the impairment of COX-2 induction and caused cell apoptosis in Beas-2B cells exposed to arsenite. Site-directed mutation of two putative NFAT binding sites between-111 to +65 in the COX-2 promoter region eliminated the COX-2 transcriptional activity induced by arsenite, confirming that those two NFAT binding sites in the COX-2 promoter region are critical for COX-2 induction by arsenite. Moreover, knockdown of COX-2 expression by COX-2-specific small interference RNA also led to an increased cell apoptosis in Beas-2B cells upon arsenite exposure. Together, our results demonstrate that COX-2 induction by arsenite is through NFAT3-dependent and AP-1- or NFkappaB-independent pathways and plays a crucial role in antagonizing arsenite-induced cell apoptosis in human bronchial epithelial Beas-2B cells.
Ding
Jin
J
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA.
Li
Jingxia
J
Xue
Caifang
C
Wu
Kangjian
K
Ouyang
Weiming
W
Zhang
Dongyun
D
Yan
Yan
Y
Huang
Chuanshu
C
D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000494:pharmacology*; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism
D018053:Arsenites; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D018808:Transcription Factor AP-1; C015001:arsenite