Tumor necrosis factor alpha induces apoptosis in mammary adenocarcinoma cells by an increase in intranuclear free Ca2+ concentration and DNA fragmentation.
The incubation of human mammary adenocarcinoma cells (BT-20) with tumor necrosis factor alpha in the absence or presence of cycloheximide resulted in progressive DNA fragmentation. This was preceded by a sustained increase in intracellular free Ca2+ concentration and was not detected in cells pretreated with intracellular Ca2+ chelators, calmodulin antagonists, or activators of protein kinase C. Image analysis of fura-2-loaded BT-20 cells treated with tumor necrosis factor alpha revealed that, in many cells, the initial increase in Ca2+ level occurred in a cellular region that corresponded to the localization of the nucleus. Our findings suggest that tumor necrosis factor alpha can promote an increase in intranuclear free Ca2+ which, in turn, may stimulate Ca(2+)-dependent endonuclease activity, resulting in DNA fragmentation and apoptosis.
Bellomo
G
G
Dipartimento di Medicina Interna e Terapia Medica, Clinica Medica I, University of Pavia, Italy.
Perotti
M
M
Taddei
F
F
Mirabelli
F
F
Finardi
G
G
Nicotera
P
P
Orrenius
S
S
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D003513:Cycloheximide / Q000494:pharmacology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D006801:Humans; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004273:DNA, Neoplasm; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; D002118:Calcium