Divergence to apoptosis from ROS induced cell cycle arrest: effect of cadmium.
Recently, the role of cadmium (Cd) in immunosupression has gained importance. Nevertheless, the signaling pathways underlying cadmium-induced immune cell death remains largely unclear. In accordance to our previous in vivo report, and to evaluate the further details of the mechanism, we have investigated the effects of cadmium (CdCl(2), H(2)O) on cell cycle regulation and apoptosis in splenocytes in vitro. Our results have revealed that reactive oxygen species (ROS) and p21 are involved in cell cycle arrest in a p53 independent manner but late hour apoptotic response was accompanied by the p53 up-regulation, loss of mitochondrial transmembrane potential (MTP), down-regulation of Bcl-xl, activation of caspase-3 and release of cytochrome c (Cyt c). However, pifithrin alfa (PFT-alpha), an inhibitor of p53, fails to rescue the cells from the cadmium-induced cell cycle arrest but prevents Bcl-xl down-regulation and loss of Deltapsi(m), which indicates that there is an involvement of p53 in apoptosis. In contrast, treatment with N-acetyl cysteine (NAC) can prevent cell cycle arrest and p21 up-regulation at early hours. Although it is clear that, NAC has no effect on apoptosis, p53 expression and MPT changes at late stage events. Taken together, we have demonstrated that cadmium promotes ROS generation, which potently initiates the cell cycle arrest at early hours and finally induces p53-dependent apoptosis at later part of the event.
Chatterjee
Soumya
S
Department of Environmental Science, University of Kalyani, West Bengal, India.
Kundu
Subhadip
S
Sengupta
Suman
S
Bhattacharyya
Arindam
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002104:Cadmium / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013053:Spectrophotometry; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D002104:Cadmium; D045304:Cytochromes c; D053148:Caspase 3