Activation of JNK, p38 and ERK mitogen-activated protein kinases by chromium(VI) is mediated through oxidative stress but does not affect cytotoxicity

Abstract

In this study we have explored the involvement of oxidative stress in Cr(VI)-induced JNK, p38 and ERK signaling pathways and their effects on Cr(VI) cytotoxicity in human non-small cell lung carcinoma CL3 cells. Exposure to K(2)Cr(2)O(7) markedly activated JNK and p38 and moderately activated ERK in a dose- (10-80 microM) and time-dependent (1-12 h) manner. The activated p38 decreased markedly and rapidly and the activated JNK decreased gradually when Cr(VI) was removed from the medium. Post-incubation of Cr(VI)-treated cells with H(2)O(2) increased the activities of JNK and p38, but not ERK. Co-administering Cr(VI) with 3-amino-1,2, 4-triazole (3AT), a catalase inhibitor, enhanced p38 activation, but did not influence JNK and ERK activation by Cr(VI). Conversely, co-administering Cr(VI) with mannitol, a hydroxyl radical scavenger and a Cr(V) chelator, reduced p38 activation and increased JNK and ERK activation by Cr(VI). These results indicate that p38 activation by Cr(VI) is positively correlated with oxidative stress, while JNK activity can be enhanced by either a quencher (mannitol) or activator (H(2)O(2)) of redox reactions in Cr(VI)-exposed CL3 cells. However, both 3AT and mannitol reduced the cytotoxicity of Cr(VI), but H(2)O(2) did not. The JNK activated by Cr(VI) was decreased (approximately 50%) by expression of a kinase-defective form of MKK7 (MKK7A) but not that of MKK4 (MKK4KR), suggesting that activation of JNK by Cr(VI) is mediated through MKK7. SB202190, a specific inhibitor of p38, markedly decreased JNK but did not change ERK activation by Cr(VI). PD98059, a specific inhibitor of ERK kinases MKK1/2, blocked ERK and p38 but did not alter JNK activation by Cr(VI). Neither the specific kinase inhibitors nor expression of MKK7A altered Cr(VI)-induced cytotoxicity. Together, these results suggest that activation of the JNK, p38 and ERK pathways by Cr(VI) is mediated through diverse redox mechanisms, yet their activation does not correlate with Cr(VI) cytotoxicity.

Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure

“…MKP5 has been shown to be able to deactivate all MAPK members, with some selectivity for the JNK/SAPK members [63,64]. Cr-induced activation of ERK, JNK and p38 pathways has been shown in a number of different cell lines, while the activation pattern is dependent on the dose/duration of the exposure [57,[65][66][67]. It has been suggested that Cr(VI) can potentially activate inhibitory MKPs [66].…”

“…Cr-induced activation of ERK, JNK and p38 pathways has been shown in a number of different cell lines, while the activation pattern is dependent on the dose/duration of the exposure [57,[65][66][67]. It has been suggested that Cr(VI) can potentially activate inhibitory MKPs [66]. The present data supports a role for Cr(VI) in MKP5 transcriptional upregulation, which may play a role in death resistance, as its upregulation was abrogated in the B-5Cr cells.…”

Hydrogen Peroxide-Induced Extracellular Signal-Regulated Kinase Activation in Cultured Feline Ileal Smooth Muscle Cells

“…The data suggest that oxidative stress initiates ERK activation by H 2 O 2 . Second, mannitol (100 mM), a free radical scavenger with specificity for hydroxyl radical (Guyton et al, 1996;Chuang et al, 2000), also abolished the ability of H 2 O 2 to activate ERKs. Third, the iron chelator o-phenanthroline (100 M) (Guyton et al, 1996;Regan et al, 2001) (Stadtman and Berlett, 1998).…”

Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1

“…Recently, p38 kinase has been implicated in the cytotoxicity of chemical carcinogens Chuang et al, 2000), scattering (Spector et al, 2000) and metastasis (Taguchi et al, 2000;Huang et al, 2000). The p38 kinase becomes activated by MKK3/6 and probably other kinases via PI3K (Raingeaud et al, 1996;Macfarlane et al, 1997).…”