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 environmental carcinogens that have been associated with lung tumors and can induce apoptosis in various cell types. Three major mitogen-activation protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK) and p38, have been shown to regulate apoptosis. In this study we explore the abilities of Cr(VI) and Cd to activate JNK, p38 and ERK, including their roles in metal-mediated growth inhibition and apoptosis in a human non-small-cell lung carcinoma cell line, CL3. Exposure to K2Cr2O7 markedly 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 low cytotoxic doses, CdCl2 decreased ERK activity with concurrently transient activation of JNK, whereas at high cytotoxic doses it persistently activated all three MAPKs. The strength and duration of JNK and p38 activated by Cd 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 cells exposed to Cr(VI) but not Cd. Both metals could increase JNK activity through 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 activators MKK1/2, greatly enhanced the cytotoxicity and apoptosis of cells treated with low Cd doses. SB202190, an inhibitor of p38, decreased the cytotoxicity 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 and that the decreased ERK signal by low Cd doses contributes to growth inhibition or apoptosis. Oppositely, activation of ERK, JNK and p38 by Cr(VI) does not affect cytotoxicity.