Exploring the proteasome system: A novel concept of proteasome inhibition and regulation

The proteasome is a well-identified therapeutic target for cancer treatment. It acts as the main protein degradation system in the cell and degrades key mediators of cell growth, survival and function. The term "proteasome" embraces a whole family of distinct complexes, which share a common proteolytic core, the 20S proteasome, but differ by their attached proteasome activators. Each of these proteasome complexes plays specific roles in the control of cellular function. In addition, distinct proteasome interacting proteins regulate proteasome activity in subcellular compartments and in response to cellular signals. Proteasome activators and regulators may thus serve as building blocks to fine-tune proteasome function in the cell according to cellular needs. Inhibitors of the proteasome, e.g. the FDA approved drugs Velcade™, Kyprolis™, Ninlaro™, inactivate the catalytic 20S core and effectively block protein degradation of all proteasome complexes in the cell resulting in inhibition of cell growth and induction of apoptosis. Efficacy of these inhibitors, however, is hampered by their pronounced cytotoxic side-effects as well as by the emerging development of resistance to catalytic proteasome inhibitors. Targeted inhibition of distinct buiding blocks of the proteasome system, i.e. proteasome activators or regulators, represents an alternative strategy to overcome these limitations. In this review, we stress the importance of the diversity of the proteasome complexes constituting an entire proteasome system. Our building block concept provides a rationale for the defined targeting of distinct proteasome super-complexes in disease. We thereby aim to stimulate the development of innovative therapeutic approaches beyond broad catalytic proteasome inhibition.