Camille Schlesser

Ludwig-Maximilians-Universität München

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Thomas Meul

Helmholtz Zentrum München

Silke Meiners

German Center for Lung Research

Fabiana Perocchi

Helmholtz Zentrum München

Christina Lukas

German Center for Lung Research

Jerzy Adamski

Helmholtz Zentrum München

Holger Prokisch

Helmholtz Zentrum München

Xinyuan Wang

Guangzhou University of Chinese Medicine

Stefanie M. Hauck

Helmholtz Zentrum München

Christine von Toerne

Helmholtz Zentrum München

Ayse Seda Yazgili

Cancer Research UK Scotland Institute

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Helmholtz Zentrum München

Ludwig-Maximilians-Universität München

Technical University of Munich

German Center for Lung Research

Center for Environmental Health

Klinikum rechts der Isar

German Center for Diabetes Research

Karolinska Institutet

Heinrich Heine University Düsseldorf

Deutsches Diabetes-Zentrum e.V.

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Mitochondrial Regulation of the 26S Proteasome

Cell Reports (2020)

Thomas Meul Korbinian Berschneider Sabine Schmitt Christoph H. Mayr Laura F. Mattner

The proteasome is the main proteolytic system for targeted protein degradation in the cell and is fine-tuned according to cellular needs. Here, we demonstrate that mitochondrial dysfunction and concomitant metabolic reprogramming of the tricarboxylic acid (TCA) cycle reduce the assembly and activity of the 26S proteasome. Both mitochondrial mutations in respiratory complex I and treatment with the anti-diabetic drug metformin impair 26S proteasome activity. Defective 26S assembly is reversible and can be overcome by supplementation of aspartate or pyruvate. This metabolic regulation of 26S activity involves specific regulation of proteasome assembly factors via the mTORC1 pathway. Of note, reducing 26S activity by metformin confers increased resistance toward the proteasome inhibitor bortezomib, which is reversible upon pyruvate supplementation. Our study uncovers unexpected consequences of defective mitochondrial metabolism for proteasomal protein degradation in the cell, which has important pathophysiological and therapeutic implications.

Protein Degradation

10.1016/j.celrep.2020.108059

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Metformin Induces Resistance of Cancer Cells to the Proteasome Inhibitor Bortezomib

Biomolecules (2022)

Camille Schlesser Thomas Meul Georgios T. Stathopoulos Silke Meiners

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.

10.3390/biom12060756

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Citations (7)