Roles of JNK, p38 and ERK mitogen-activated protein kinases in the growth inhibition and apoptosis induced by cadmium

Cadmium (Cd), a human carcinogen, can induce apoptosis in various cell type s. Three major mitogen-activated protein kinases (MAPKs), c-JUN N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase (ERK), have bee n shown to regulate apoptosis, In this study we explore the ability of Cd t o activate JNK, p38 and ERK, including their effects on Cd-mediated growth inhibition and apoptosis in a human non-small cell lung carcinoma cell line , CL3, The kinase activity of JNK was induced dose-dependently by 30-160 mu M CdCl2. Nigh cytotoxic doses of Cd (130-160 mu M) markedly activated p38, but low Cd doses did not. Conversely, the activities of ERK1 and ERK2 were decreased by low cytotoxic doses of Cd (less than or equal to 80 mu M) and moderately activated by high Cd doses. Low cytotoxic doses of Cd transient ly activated JNK and simultaneously reduced ERK activity, whereas high cyto toxic doses of Cd persistently activated JNK and p38, PD98059, an inhibitor of ERK upstream activators MAPK kinase (MKK) 1 and MKK2, greatly enhanced cytotoxicity and apoptosis in cells treated with low Cd doses. In contrast, SB202190, an inhibitor of p38, decreased the cytotoxicity and apoptosis in duced by high Cd doses, Transient expression of a dominant negative form of JNK1, but not that of JNK2, significantly increased the viability and prev ented apoptosis of Cd-treated cells. However, expression of wild-type JNK1 did not affect viability and apoptosis of Cd-treated cells, Transfection of wild-type JNK2 or p38 enhanced apoptosis of cells exposed to low Cd doses but did not affect those exposed to high Cd doses. The JNK activity stimula ted by low Cd doses was partially suppressed by expression of a dominant ne gative form of MKK7, but not a dominant negative form of MKK4, indicating t hat MKK7 is involved in JNK activation by Cd, Together, the results of this study suggest that JNK and p38 cooperatively participate in apoptosis indu ced by Cd and that the decreased ERK signal induced by low Cd doses contrib utes to growth inhibition or apoptosis.