FIG. 3.

Proteasome inhibitor–induced apoptosis and potential sites of ROS generation. The proteasome inhibitor, bortezomib, and its structurally similar relative, MG132, have been found to increase intracellular ROS levels. At least two explanations have been offered for this observation. An accumulation of polyubiquitinated proteins overwhelms the protein-handling machinery of the cell, causing endoplasmic reticular (ER) stress, which may then cause oxidative stress. Mitochondrial perturbations by proteasome inhibitors can cause release of mitochondrial resident oxidants and cytochrome c, promoting caspase activation. A connection between these two pathways is depicted by the dashed line and includes the ability of ROS generated from mitochondria to cause ER stress.