Trivalent chromium activates Rac-1 and Src and induces switch in the cell death mode in human dermal fibroblasts.
In this study we examined interactions between human dermal fibroblasts and chromium acetate hydroxide originating from environmental waste sediments. We show that initially exposure of fibroblasts to Cr (III) induced membrane-dependent signaling including activation of Rac1 GTPase, Src and apoptosis signal-regulating kinase 1 (ASK-1) kinases leading to increased activities of p38 and particularly Jun N-terminal kinase (JNK) and subsequent activation of caspase-3. At later treatment intervals (48-96 h), caspase-3 activity became suppressed and markedly increased lactate dehydrogenase (LDH) release was observed. Further experiments demonstrated that LDH release occurred in the presence of increased oxidative stress, extensive DNA damage, overactivation of poly(ADP-ribose)polymerase-1 (PARP-1) and depletion of ATP. Using specific inhibitors it was demonstrated that oxidative stress along with PARP-1 activity are responsible for cell death mode switch and upon their inhibition caspase-3 activity could be restored. In conclusion, Cr (III) seems to induce a biphasic response in dermal fibroblasts, with initial apoptosis switched to necrosis via increased DNA damage and resulting PARP-1 activity.
Rudolf
Emil
E
Department of Medical Biology and Genetics, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Simkova 870, Hradec Kralove 500 38, Czech Republic. rudolf@lfhk.cuni.cz
Cervinka
Miroslav
M
D000085:Acetates / Q000633:toxicity*; D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000096:biosynthesis / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002857:Chromium / Q000633:toxicity*; D004249:DNA Damage; D004785:Environmental Pollutants / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000378:metabolism; D012037:Refuse Disposal; D012867:Skin / Q000166:cytology*; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis / Q000378:metabolism*; D019061:src-Family Kinases / Q000096:biosynthesis / Q000378:metabolism*
D000085:Acetates; D004785:Environmental Pollutants; C107953:RAC1 protein, human; D002857:Chromium; D000255:Adenosine Triphosphate; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019061:src-Family Kinases; D053148:Caspase 3; D020830:rac1 GTP-Binding Protein