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

Abstract

Cadmium (Cd), a human carcinogen, can induce apoptosis in various cell types. Three major mitogen-activated protein kinases (MAPKs), c-JUN N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase (ERK), have been shown to regulate apoptosis. In this study we explore the ability of Cd to 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 microM CdCl(2). High cytotoxic doses of Cd (130-160 microM) markedly activated p38, but low Cd doses did not. Conversely, the activities of ERK1 and ERK2 were decreased by low cytotoxic doses of Cd (</=80 microM) and moderately activated by high Cd doses. Low cytotoxic doses of Cd transiently activated JNK and simultaneously reduced ERK activity, whereas high cytotoxic 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 induced by high Cd doses. Transient expression of a dominant negative form of JNK1, but not that of JNK2, significantly increased the viability and prevented 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 stimulated by low Cd doses was partially suppressed by expression of a dominant negative form of MKK7, but not a dominant negative form of MKK4, indicating that MKK7 is involved in JNK activation by Cd. Together, the results of this study suggest that JNK and p38 cooperatively participate in apoptosis induced by Cd and that the decreased ERK signal induced by low Cd doses contributes to growth inhibition or apoptosis.

In vitro effect of cadmium and copper on separated blood leukocytes of Dicentrarchus labrax

“…Several reports have shown that cadmium induces apoptosis in various tissues and cells, both in vivo and in vitro (Hamada et al, 1997). E.g., cadmium-induced apoptosis was reported in rat testes (Xu et al, 1996), mouse liver (Habeebu et al, 1998), rat lung epithelial cells (Hart et al, 1999), CL-3 human lung carcinoma cells (Chuang et al, 2000), HeLa human cervix carcinoma cells (Szuster-Ciesielska et al, 2000) and Rat-1 fibroblast cells (Kim et al, 2000). Copper, for its part, can induce an upregulation of apoptosis and related genes in zebrafish (Luzio et al, 2013) or induces the apoptotic cell death in the copepod Tigriopus japonicus (Rhee et al, 2013).…”

Examination of the Cellular Mechanisms by Which Marinobufagenin Inhibits Cytotrophoblast Function

“…Berra et al (64) demonstrated that inhibition of basal ERK activity is sufficient to trigger apoptosis and p38 activation with no changes in Jnk phosphorylation. Chuang et al (65) showed that CdCl 2 activated Jnk and p38 signaling with a concomitant decrease in ERK signaling. The stimulated Jnk and p38 pathways are known to regulate cell proliferation, invasion, survival, migration, growth arrest, and apoptosis (41, 20 -24).…”

ERK1/2 Achieves Sustained Activation by Stimulating MAPK Phosphatase-1 Degradation via the Ubiquitin-Proteasome Pathway

“…The BCA protein assay kit (Pierce) was employed to determine protein concentrations using bovine serum albumin as a standard. Equal amounts of proteins from each set of experiments were subjected to Western blot analysis as described (31). Antibodies were stripped from polyvinylidene difluoride membranes using a solution containing 2% SDS, 62.5 mM Tris-HCl, pH 6.8, and 0.7% (w/w) ␤-mercaptoethanol at 50°C for 15 min before re-probing with another primary antibody.…”