MT-21 is a synthetic apoptosis inducer that directly induces cytochrome c release from mitochondria.
We reported previously that a synthetic compound, MT-21, induced apoptosis by activating c-Jun-NH2-terminal kinase via the Krs/MST protein, which is activated by caspase-3 cleavage dependent on reactive oxygen species production. Here we examine the activation mechanism of caspase-3, an important cysteine aspartic protease, during MT-21-induced apoptosis. We found that MT-21 activated caspase-3 via caspase-9, but not via caspase-8. In addition, MT-21 induced the release of cytochrome c from the mitochondria that is necessary to activate caspase-9, and this release occurred before a change in membrane potential. This initiation process of MT-21-induced apoptosis was suppressed by overexpression of Bcl-2, which is known to prevent cells from undergoing apoptosis in response to a variety of stimuli. Moreover, when we treated mitochondria isolated from the cells with MT-21, the direct release of cytochrome c from the mitochondria was observed, whereas this effect was not observed in the mitochondria isolated from cells that overexpressed Bcl-2. Other apoptosis-inducing agents known to induce apoptosis via cytochrome c release from the mitochondria failed to release cytochrome c directly from isolated mitochondria. These findings indicate that MT-21 is a possible candidate antitumor agent that is able to induce apoptosis via the direct release of cytochrome c from the mitochondria.
Watabe
M
M
Antibiotics Laboratory, Riken Institute, Saitama, Japan.
Machida
K
K
Osada
H
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002474:Cell-Free System; D003574:Cytochrome c Group / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011758:Pyrroles / Q000494:pharmacology*; D020298:U937 Cells
D000970:Antineoplastic Agents; D003574:Cytochrome c Group; C121809:MT 21; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases