T-2 toxin initially activates caspase-2 and induces apoptosis in U937 cells.
T-2 toxin, which belongs to a group of mycotoxins synthesized by Fusarium fungi that are widely encountered as natural contaminants, induced apoptosis with distinct morphological and biological features in U937 cells. The concentration of more than 10nM T-2 toxin affected cell viability, induced nuclear and DNA fragmentation and caspase-3 activation. Caspase-2, -3, -8, and -9 were activated during T-2 toxin-induced apoptosis. T-2 toxin neither inhibited mitochondrial respiratory chain complexes I-IV in isolated mitochondria nor decreased ATP levels in U937 cells. Both enzyme activity assay and Western blot analysis revealed that T-2 toxin activated caspase-2 earlier than caspase-3, -8, and -9. Caspase-2 inhibitor (VDVAD-CHO/fmk) and caspase-8 inhibitor (IETD-CHO/fmk) completely blocked the T-2 toxin-induced process of procaspase-3, while caspase-9 inhibitor (LEHD-CHO/fmk) did so less effectively. Caspase-2 inhibitor entirely blocked T-2 toxin-induced caspase-8, and -9 activation. These results clearly indicate that activation of caspase-2 is essential to T-2 toxin-induced apoptosis and that apoptotic signals are mainly transmitted via caspase-8 and caspase-3 rather than mitochondrial pathway.
Huang
Peixin
P
Department of Social and Environmental Medicine, Osaka University Graduate School of Medicine, Yamada-Oka 2-2, Suita, Osaka 565-0871, Japan.
Akagawa
Keisuke
K
Yokoyama
Yoshiko
Y
Nohara
Kazunari
K
Kano
Kazutaka
K
Morimoto
Kanehisa
K
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053143:Caspase 2 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D013605:T-2 Toxin / Q000633:toxicity*; D020298:U937 Cells
D000255:Adenosine Triphosphate; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases; D013605:T-2 Toxin