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Human & Experimental Toxicology, Vol. 22, No. 3, 111-123 (2003)
DOI: 10.1191/0960327103ht322oa

Fluoride-induced apoptosis in human epithelial lung cells (A549 cells): role of different G protein-linked signal systems

Magne Refsnes

Division of Environmental Medicine, National Institute of Public Health, Geitmyrsvn. 75, PO Box 4404 Nydalen, N-0403 Oslo, Norway; magne.refsnes{at}fhi.no

Per E Schwarze

Jørn A Holme

Marit Laêg

Division of Environmental Medicine, Norwegian Institute of Public Health, Geitmyrsvn. 75, PO Box 4404 Nydalen, N-0403 Oslo, Norway

In the present study, possible mechanisms involved in fluoride-induced apoptosis in a human epithelial lung cell line (A549) were examined. Sodium fluoride (NaF) induced apoptosis in the A549 cells, with a maximum at 5-7.5 mM after 20 hours of exposure. The number of cells with plasma membrane damage (PI-positive cells) increased moderately up to 5 mM, but markedly at 7.5 mM. Deferoxamine (an Al3 chelator) almost completely prevented these NaF-induced responses, which may suggest a role for G protein activation. The apoptotic effect was partially reduced by the PKA inhibitor H89. NaF induced a weak but sustained increase in PKC activity, whereas the PKC activator TPA induced a transient effect. TPA, which enhanced the NaF-induced PKC activity, was not apoptotic when added alone, but facilitated the NaFinduced apoptosis and the increase in PI-positive cells. PKC downregulation induced by TPA pretreatment almost completely prevented the NaF-induced apoptosis and the increase in PI-positive cells. Pretreatment with the PKC inhibitor GF109203X, which abolished the PKC activity after 3 hours, enhanced the NaF-induced apoptosis. KN93 (a CaM kinase II inhibitor) and W7 (a calmodulin inhibitor) seem to reduce the apoptotic effect of NaF, whereas BAPTA-AM (a Ca2 chelator) was without effect. The tyrosine kinase inhibitor genistein also markedly reduced the NaF-induced apoptosis, whereas the PI-3 kinase inhibitor wortmannin augmented the response. In conclusion, the present results suggest that NaF induces an apoptotic effect and an increase in PI-positive A549 cells via similar mechanisms, involving PKC, PKA, tyrosine kinase and Ca2 linked enzymes, whereas PI-3 kinase seems to exert a counteracting effect.

Key Words: apoptosis • A549 cells • fluoride • signal transducing mechanisms


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