Curcumin induces caspase-3-dependent apoptotic pathway but inhibits DNA fragmentation factor 40/caspase-activated DNase endonuclease in human Jurkat cells.
Curcumin is a natural pigment that has been shown to induce cell death in many cancer cells; however, the death mode depends on the cell type and curcumin concentration. Here we show that, in Jurkat cells, 50 micromol/L curcumin severely lowers cell survival and induces initial stage of chromatin condensation. It also induces caspase-3, which is sufficient to cleave DNA fragmentation factor 45 [DFF45/inhibitor of caspase-activated DNase (ICAD)], the inhibitor of DFF40/CAD endonuclease. However, the release of DFF40/CAD from its inhibitor does not lead to oligonucleosomal DNA degradation in curcumin-treated cells. Moreover, curcumin treatment protects cells from UVC-induced oligonucleosomal DNA degradation. In biochemical experiments using recombinant DFF activated with caspase-3, we show that curcumin inhibits plasmid DNA and chromatin degradation although it does not prevent activation of DFF40/CAD endonuclease after its release from the inhibitor. Using DNA-binding assay, we show that curcumin does not disrupt the DNA-DFF40/CAD interaction. Instead, molecular modeling indicates that the inhibitory effect of curcumin on DFF40/CAD activity results from curcumin binding to the active center of DFF40/CAD endonuclease.
Sikora
Ewa
E
Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, 3 Pasteura, 02-093 Warsaw, Poland. e.sikora@nencki.gov.pl
Bielak-Zmijewska
Anna
A
Magalska
Adriana
A
Piwocka
Katarzyna
K
Mosieniak
Grazyna
G
Kalinowska
Magdalena
M
Widlak
Piotr
P
Cymerman
Iwona A
IA
Bujnicki
Janusz M
JM
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D003474:Curcumin / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects*; D003851:Deoxyribonucleases / Q000037:antagonists & inhibitors*; D006801:Humans; D019169:Jurkat Cells; D011506:Proteins / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D011506:Proteins; C109664:caspase-activated DNase inhibitor; D003851:Deoxyribonucleases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003474:Curcumin