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Dissociation of Staurosporine-induced Apoptosis from G₂-M Arrest in SW620 Human Colonic Carcinoma Cells: Initiation of the Apoptotic Cascade Is Associated with Elevation of the Mitochondrial Membrane Potential (_m)¹

Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467

We have identified an alternative apoptotic cascade induced in SW620 human colonic carcinoma cells by the protein kinase antagonist staurosporine (stsp). Consistent with its effect in other colonic epithelial cells, stsp induced G₂-M arrest and apoptosis of SW620 cells. However, despite the paradigm that growth arrest triggers apoptotic cascades, apoptosis was detected before G₂-M arrest. Reports have linked dissipation of the mitochondrial membrane potential (_m) to the initiation of apoptosis and have linked elevation of the _m to the escape from apoptosis. However, neither apoptosis nor cell cycle arrest were altered by the collapse of the _m, and increased _m enhanced the initiation of apoptosis but blocked G₂-M arrest. Although reactive oxygen species (ROS) have been implicated in some colonic epithelial cell and stsp-induced cascades, neither antioxidants nor the inhibition of RNA or protein synthesis altered apoptosis of SW620 cells. Finally, cytosolic cytochrome c has been linked to activation of caspase-3 and dissipation of the _m. However, caspase-3 activation preceded the accumulation of cytochrome c in the cytosol and was accompanied by transient elevations in both the _m and mitochondria-associated cytochrome c. Therefore, we have identified a distinct apoptotic cascade in SW620 cells that was induced independently of growth arrest, dissipation of the _m, ROS production, or synthesis of de novo RNA or protein, and we have linked its efficient initiation to early elevation of the _m.

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