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Carcinogenesis, Vol. 20, No. 9, 1683-1688, September 1999
© 1999 Oxford University Press

Cancer Biology

Activation of mitogen-activated protein kinase by fumonisin B1 stimulates cPLA2 phosphorylation, the arachidonic acid cascade and cAMP production

Eric Pinelli, Nathalie Poux, Liliane Garren1, Bernard Pipy2, Marcel Castegnaro1, David J. Miller3 and Annie Pfohl-Leszkowicz4

ENSAT, Laboratoire de Toxicologie et Sécurité Alimentaire, 1 avenue Agrobiopole, BP 107, 31326 Auzeville-Tolosane,
1 Unit of Gene–Environment Interactions, IARC, 150 cours Albert Thomas, 69008 Lyon,
2 CHU Rangueil, Laboratoire d'Etude du Macrophage, avenue Jean Poulhies, 31400 Toulouse, France and
3 Department of Chemistry, 228 Steacie Building, Carleton University, Ottawa, Ontario K1S 5B6, Canada

Activation of mitogen-activated protein kinase (MAPK) results in pleiotropic effects such as modulation of the transcription and activation of enzymes involved in signal transduction. One such enzyme is the cytoplasmic phospholipase A2 (cPLA2), which releases arachidonic acid (AA). AA is the precursor of prostaglandins and leukotrienes, two inflammatory mediators, which regulate gene expression and protein kinase (PK) activity. Fumonisin B1 (FB1) was shown to increase PKC translocation and stimulate MAPK. We have investigated the effect of FB1 on the AA cascade in a human epithelial cell line and the signal transduction pathway regulating PLA2 activation. We observed that FB1 stimulated cPLA2 activity and increased AA release by a mechanism independent of PKC activation and that the activation of cPLA2 is a two-step process: the first is phosphorylation of cPLA2 by MAPK; the second is a consequence of the increase in sphingosine inside and outside the cells after 2 h, which is known to induce a rise in intracellular free calcium. Overall, this suggests that the effect of FB1 on cells is partially dependent on the action of FB1 on the enzymes involved in the cell cycle, such as MAPK and PKA, and on bioactive fatty acids, such as the prostaglandins and leukotrienes, and also on disruption of sphingolipid metabolism. In addition, we have observed down-regulation of cPLA2 activity and AA metabolism by a mechanism involving prostaglandin production, cAMP synthesis and PKA activation.

Abbreviations: AA, arachidonic acid; cAMP, cyclic adenosine 3',5'-monophosphate; cPLA2, cytoplasmic phospholipase A2; EMEM, Eagle's minimal essential medium; FB1, fumonisin B1; H89, N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide; HETE, hydroxyeicosatetraenoic acid; LT, leukotriene; MAPK, mitogen-activated protein kinase; OPA, o-phthaldialdehyde; PBS, phosphate-buffered saline; PG, prostaglandin; PKA, cAMP-dependent protein kinase; PKC, protein kinase C; Sa, sphinganine; So, sphingosine.

4 To whom correspondence should be addressedEmail: leszkowicz{at}ensat.fr


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