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

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 (Dcm) to the initiation of apoptosis and have linked elevation of the Dcm to the escape from apoptosis. However, neither apoptosis nor cell cycle arrest were altered by the collapse of the Dcm, and increased Dcm 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 Dcm. However, caspase-3 activation preceded the accumulation of cytochrome c in the cytosol and was accompanied by transient elevations in both the Dcm 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 Dcm, ROS production, or synthesis of de novo RNA or protein, and we have linked its efficient initiation to early elevation of the Dcm.