Stimulation of p38 Mitogen-activated Protein Kinase Is an Early Regulatory Event for the Cadmium-induced Apoptosis in Human Promonocytic Cells

Abstract

Pulse treatment of U-937 promonocytic cells with cadmium chloride (2 h at 200 M) provoked apoptosis and induced a rapid phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK ) as well as a late phosphorylation of extracellular signal-regulated protein kinases (ERK1/2). However, although the p38 MAPK -specific inhibitor SB203580 attenuated apoptosis, the process was not affected by the ERK-specific inhibitor PD98059. The attenuation of the cadmium-provoked apoptosis by SB203580 was a highly specific effect. In fact, the kinase inhibitor did not prevent the generation of apoptosis by heat shock and camptothecin, nor the generation of necrosis by cadmium treatment of glutathione-depleted cells, nor the cadmium-provoked activation of the stress response. The generation of apoptosis was preceded by intracellular H 2 O 2 accumulation and was accompanied by the disruption of mitochondrial transmembrane potential, both of which were inhibited by SB203580. On the other hand, the antioxidant agent butylated hydroxyanisole-inhibited apoptosis but did not prevent p38 MAPK phosphorylation. In a similar manner, p38 MAPK phosphorylation was not affected by the caspase inhibitors Z-VAD and DEVD-CHO, which nevertheless prevented apoptosis. These results indicate that p38 MAPK activation is an early and specific regulatory event for the cadmium-provoked apoptosis in promonocytic cells.Cadmium and other heavy metals are frequent environmental contaminants with well known mutagenic, carcinogenic, and teratogenic effects (1). Another property of heavy metals (and of other physical and chemical agents, such as heat and inhibitors of energy metabolism) is the capacity to induce the stress response, characterized by the synthesis and accumulation of heat-shock proteins (HSPs)

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

“…Many reports suggested that JNK or p38 MAPK induces apoptosis by regulating the translocation of Bax from the cytoplasm to the mitochondria in response to various stimuli (12)(13)(14). These results are consistent with the fact that JNK and/ or p38 MAPK acts at early step before dysfunction of mitochondria and caspase activation in several cell types (15)(16)(17). In contrast, recent observations showed that p38 MAPK is a critical regulator of cell survival and proliferation in response to cisplatin, camptothecin, doxorubicin, UV irradiation, and repetitive low-grade oxidative stress (18)(19)(20).…”

“…Many reports suggested that p38 MAPK induces apoptotic cell death in response to various stimuli (15)(16)(17). In contrast, in this study we showed that p38 MAPK played a role in cell survival response against radiation-induced mitochondrial cell death.…”

Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine

“…Furthermore, ERK expression in NIH 3T3 cells impairs the majority of the UV-induced apoptotic response (14). The prosurvival function of ERK was confirmed in a recent report showing that inhibition of ERK signaling leads to increased sensitivity to cisplatin (cis-diammine-dichloroplatinum) in ovarian cancer cells (31). Conversely, activation of the MEK/ ERK signaling pathway in activated Jurkat T cells suppresses tumor necrosis factor-related apoptosis-inducing ligand -mediated apoptosis in a similar manner to Fas-mediated apoptosis (30).…”

Protein kinase C inhibits singlet oxygen-induced apoptosis by decreasing caspase-8 activation

“…However, p38 was not associated with activation of caspase-8 in exerting such roles , suggesting that at least two parallel signaling pathways exist above Bid. Recently, it has been shown that p38 activation is also required for the release of cytochrome c from mitochondria in the apoptosis induced by cadmium and UV light, supporting the idea that p38 functions upstream of mitochondria in mediating activation of caspase-3 (Assefa et al, 2000;Galan et al, 2000). In the case of singlet oxygen, caspase-3 activation is su cient for induction of apoptosis (Zhuang et al, 1999); thus, inactivation of caspase-8 and/or p38 pathways may allow cells to escape apoptosis following singlet oxygen treatment.…”