RESUMO
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.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Linfoma de Célula do Manto , Metformina , Adulto , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antivirais/uso terapêutico , Ácidos Borônicos/farmacologia , Bortezomib/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Metformina/farmacologia , Metformina/uso terapêutico , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Pirazinas/farmacologiaRESUMO
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.
