Involvement of the extracellular signal-regulated protein kinase (ERK) pathway in the induction of apoptosis by cadmium chloride in CCRF-CEM cells

When CCRF-CEM cells were incubated with 5-40 muM CdCl2 apoptosis was observed mast clearly at 10 muM. Prior to the development of apoptosis, mitogen-activated protein kinases (MAPKs), i.e. extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, were activated with different sensitivity to CdCl2 exposure. ERK and p38 MAPK were phosphorylated with incubation of 1 muM CdCl2 but higher than 20 muM CdCl2 was required for the clear phosphorylation of JNK. In the time- course study, ERK and p38 MAPK were phosphorylated earlier than JNK after CdCl2 exposure. The in vitro activities of MAPKs also increased in response to CdCl2 exposure. Pretreatment with an intracellular Ca2+ chelator, 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA/AM), suppressed almost completely CdCl2-induced phosphorylation of INK and p38 MAPK, but not ERK phosphorylation, indicating that the activation of JNK and p38 MAPK depends on the intracellular Ca2+ but that of ERK does not. On the other hand, treatment with a MAPK/ERK kinase (MEK) inhibitor, U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene), suppressed CdCl2-induced ERK activation and the apoptosis as well. The inhibition of p38 MAPK activity with SB203580 (4-[4-fluorophenyl]-2-[4-methylsulfinylphenyl]-5-[4-pyridyl]1H-imidazole) did not protect cells from apoptosis. The present results showed that the activation of ERK, JNK, and p38 MAPK is differently regulated in CCRF-CEM cells exposed to CdCl2 and that the ERK pathway seems to be responsible for the induction of apoptosis by CdCl2 exposure in this human T cell line. BIOCHEM PHARMACOL 60;12:1875-1882, 2000. (C) 2000 Elsevier Science Inc.