Comparison of roles of three mitogen-activated protein kinases induced by chromium(VI) and cadmium in non-small-cell lung carcinoma cells

Chromium(VI) 'Cr(VI)' and cadmium (Cd) compounds are ubiquitous environment al carcinogens that have been associated with lung tumors and can induce ap optosis in various cell types. Three major mitogen-activation protein kinas es (MAPKs), extracellular signal-regulated kinase (ERK), c-JUN N-terminal k inase (JNK) and p38, have been shown to regulate apoptosis. In this study w e explore the abilities of Cr(VI) and Cd to activate JNK, p38 and ERK, incl uding their roles in metal-mediated growth inhibition and apoptosis in a hu man non-small-cell lung carcinoma cell line, CL3. Exposure to K2Cr2O7 marke dly activated JNK and p38 and moderately activated ERK in a dose- and time- dependent manner. The activated p38 decreased markedly and rapidly and the activated JNK decreased gradually when Cr(VI) was removed from media. At lo w cytotoxic doses, CdCl2 decreased ERK activity with concurrently transient activation of JNK, whereas at high cytotoxic doses it persistently activat ed all three MAPKs. The strength and duration of JNK and p38 activated by C d were higher and longer than Cr(VI) did when compared at similar cytotoxic doses. In comparable experiment conditions Cd is a much stronger apoptotic inducer than Cr(VI) in CL3 cells. Cross-talk of MAPKs was observed in cell s exposed to Cr(VI) but not Cd. Both metals could increase JNK activity thr ough MKK7 but not MKK4. The Cd-activated JNK is involved in apoptosis, but the Cr-activated JNK is not. PD98059, an inhibitor of the ERK upstream acti vators MKK1/2, greatly enhanced the cytotoxicity and apoptosis of cells tre ated with low Cd doses. SB202190, an inhibitor of p38, decreased the cytoto xicity and apoptosis induced by high Cd doses. Conversely, neither SB202190 nor PD98059 altered Cr(VI)-induced cytotoxicity. The results suggest that JNK and p38 signals cooperatively participate in apoptosis induced by Cd an d that the decreased ERK signal by low Cd doses contributes to growth inhib ition or apoptosis. Oppositely, activation of ERK, JNK and p38 by Cr(VI) do es not affect cytotoxicity.