Metformin Induces Resistance of Cancer Cells to the Proteasome Inhibitor Bortezomib.

The anti-diabetic drug metformin is currently tested for the treatment of hematological and solid cancers. Proteasome inhibitors, e.g., Bortezomib, are approved for the treatment of multiple myeloma and mantle cell lymphoma but are also studied for lung cancer therapy. We here analyzed the interaction of the two drugs in two cell lines, namely the mantle cell lymphoma Jeko-1 and the non-small-cell lung cancer (NSCLC) H1299 cells, using proliferation and survival assays, native-gel analysis for proteasome activity and assembly, and expression analysis of proteasome assembly factors. Our results demonstrate that metformin treatment induces resistance of cancer cells to the proteasome inhibitor Bortezomib by impairing the activity and assembly of the 26S proteasome complexes. These effects of metformin on proteasome inhibitor sensitivity in cancer cells are of potential relevance for patients that receive proteasome inhibitor therapy.

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.

Proteasome activator PA200 regulates myofibroblast differentiation.

The proteasome is essential for the selective degradation of most cellular proteins and is fine-tuned according to cellular needs. Proteasome activators serve as building blocks to adjust protein turnover in cell growth and differentiation. Understanding the cellular function of proteasome activation in more detail offers a new strategy for therapeutic targeting of proteasomal protein breakdown in disease. The role of the proteasome activator PA200 in cell function and its regulation in disease is unknown. In this study, we investigated the function of PA200 in myofibroblast differentiation and fibrotic tissue remodeling. PA200 was upregulated in hyperplastic basal cells and myofibroblasts of fibrotic lungs from patients with idiopathic pulmonary fibrosis. Increased expression of PA200 and enhanced formation of PA200-proteasome complexes was also evident in experimental fibrosis of the lung and kidney in vivo and in activated primary human myofibroblasts of the lung in vitro. Transient silencing and overexpression revealed that PA200 functions as a negative regulator of myofibroblast differentiation of human but not mouse cells. Our data thus suggest an unexpected and important role for PA200 in adjusting myofibroblast activation in response to pro-fibrotic stimuli, which fails in idiopathic pulmonary fibrosis.