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Activation of both nuclear factor of activated T cells and inhibitor of nuclear factor-kappa B kinase beta-subunit-/nuclear factor-kappa B is critical for cyclooxygenase-2 induction by benzo[a]pyrene in human bronchial epithelial cells.
Cancer Sci. 2007 Sep; 98(9):1323-9.CS

Abstract

The carcinogenic effect of benzo[a]pyrene (B[a]P), presenting mainly in cigarette smoke and air pollution, has been well demonstrated both in vitro and in vivo. However, it is still not well understood how B[a]P facilitates pulmonary carcinogenesis. To explore this, we investigated the effect of B[a]P on the induction of cyclooxygenase-2 (COX-2), a critical enzyme implicated in inflammation and cancer development, as well as upstream signaling pathways leading to its expression in human bronchial epithelial cells (Beas-2B). We found that exposure of Beas-2B to B[a]P caused significant COX-2 induction at both the transcriptional and protein levels. B[a]P also switched on the nuclear factor of activated T cells (NFAT) and nuclear factor kappaB (NF-kappaB) signaling pathways. B[a]P-induced COX-2 expression was significantly blocked by inhibition of the NFAT pathway, and impairment of the NF-kappaB signaling pathway by ectopic expression of an inhibitor of nuclear factor-kappaB kinase beta-subunit (IKKbeta) kinase inactive mutant (IKKbeta-KM) also dramatically inhibited COX-2 induction. The IKKbeta/NF-kappaB-dependent COX-2 induction was further confirmed in mouse embryonic fibroblasts with IKKbeta deficiency (IKKbeta(-/-)) and in those that expressed reconstituted IKKbeta. However, activation of the NFAT and NF-kappaB signaling pathways by B[a]P were independent of each other, as blocking one signaling pathway didn't interrupt the activation of the other one. Mutation of either NFAT or NF-kappaB binding sites significantly blocked COX-2 promoter induction by B[a]P. Taken together, these data indicate that exposure of Beas-2B to B[a]P can upregulate COX-2 expression by increasing its transcription, which requires activation of both the NFAT and NF-kappaB signaling pathways.

Authors+Show Affiliations

Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17640307

Citation

Ding, Jin, et al. "Activation of Both Nuclear Factor of Activated T Cells and Inhibitor of Nuclear Factor-kappa B Kinase Beta-subunit-/nuclear Factor-kappa B Is Critical for Cyclooxygenase-2 Induction By Benzo[a]pyrene in Human Bronchial Epithelial Cells." Cancer Science, vol. 98, no. 9, 2007, pp. 1323-9.
Ding J, Wu K, Zhang D, et al. Activation of both nuclear factor of activated T cells and inhibitor of nuclear factor-kappa B kinase beta-subunit-/nuclear factor-kappa B is critical for cyclooxygenase-2 induction by benzo[a]pyrene in human bronchial epithelial cells. Cancer Sci. 2007;98(9):1323-9.
Ding, J., Wu, K., Zhang, D., Luo, W., Li, J., Ouyang, W., Song, L., & Huang, C. (2007). Activation of both nuclear factor of activated T cells and inhibitor of nuclear factor-kappa B kinase beta-subunit-/nuclear factor-kappa B is critical for cyclooxygenase-2 induction by benzo[a]pyrene in human bronchial epithelial cells. Cancer Science, 98(9), 1323-9.
Ding J, et al. Activation of Both Nuclear Factor of Activated T Cells and Inhibitor of Nuclear Factor-kappa B Kinase Beta-subunit-/nuclear Factor-kappa B Is Critical for Cyclooxygenase-2 Induction By Benzo[a]pyrene in Human Bronchial Epithelial Cells. Cancer Sci. 2007;98(9):1323-9. PubMed PMID: 17640307.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of both nuclear factor of activated T cells and inhibitor of nuclear factor-kappa B kinase beta-subunit-/nuclear factor-kappa B is critical for cyclooxygenase-2 induction by benzo[a]pyrene in human bronchial epithelial cells. AU - Ding,Jin, AU - Wu,Kangjian, AU - Zhang,Dongyun, AU - Luo,Wenjing, AU - Li,Jingxia, AU - Ouyang,Weiming, AU - Song,Lun, AU - Huang,Chuanshu, Y1 - 2007/07/19/ PY - 2007/7/21/pubmed PY - 2007/10/18/medline PY - 2007/7/21/entrez SP - 1323 EP - 9 JF - Cancer science JO - Cancer Sci VL - 98 IS - 9 N2 - The carcinogenic effect of benzo[a]pyrene (B[a]P), presenting mainly in cigarette smoke and air pollution, has been well demonstrated both in vitro and in vivo. However, it is still not well understood how B[a]P facilitates pulmonary carcinogenesis. To explore this, we investigated the effect of B[a]P on the induction of cyclooxygenase-2 (COX-2), a critical enzyme implicated in inflammation and cancer development, as well as upstream signaling pathways leading to its expression in human bronchial epithelial cells (Beas-2B). We found that exposure of Beas-2B to B[a]P caused significant COX-2 induction at both the transcriptional and protein levels. B[a]P also switched on the nuclear factor of activated T cells (NFAT) and nuclear factor kappaB (NF-kappaB) signaling pathways. B[a]P-induced COX-2 expression was significantly blocked by inhibition of the NFAT pathway, and impairment of the NF-kappaB signaling pathway by ectopic expression of an inhibitor of nuclear factor-kappaB kinase beta-subunit (IKKbeta) kinase inactive mutant (IKKbeta-KM) also dramatically inhibited COX-2 induction. The IKKbeta/NF-kappaB-dependent COX-2 induction was further confirmed in mouse embryonic fibroblasts with IKKbeta deficiency (IKKbeta(-/-)) and in those that expressed reconstituted IKKbeta. However, activation of the NFAT and NF-kappaB signaling pathways by B[a]P were independent of each other, as blocking one signaling pathway didn't interrupt the activation of the other one. Mutation of either NFAT or NF-kappaB binding sites significantly blocked COX-2 promoter induction by B[a]P. Taken together, these data indicate that exposure of Beas-2B to B[a]P can upregulate COX-2 expression by increasing its transcription, which requires activation of both the NFAT and NF-kappaB signaling pathways. SN - 1347-9032 UR - https://www.unboundmedicine.com/medline/citation/17640307/Activation_of_both_nuclear_factor_of_activated_T_cells_and_inhibitor_of_nuclear_factor_kappa_B_kinase_beta_subunit_/nuclear_factor_kappa_B_is_critical_for_cyclooxygenase_2_induction_by_benzo[a]pyrene_in_human_bronchial_epithelial_cells_ L2 - https://doi.org/10.1111/j.1349-7006.2007.00530.x DB - PRIME DP - Unbound Medicine ER -