Metabolic silencing via methionine-based amino acid restriction in multiple myeloma cell lines reveals a potential new strategy for cancer therapy

Abstract

Nutrient restriction, from caloric to amino acid to protein restriction, promotes cell switching to low-energy metabolism (LEM), which is characterized primarily by inhibited cell proliferation. In the long term, nutrient restriction has enormous impacts on life span and age-associated diseases such as type 2 diabetes and cancer. Owing to their antiproliferative effects, nutrient restriction approaches with a focus on amino acids are receiving increasing attention for use in tumour therapy. However, to date, the effects of amino acid restriction (AAR) have rarely been reported in patients with multiple myeloma (MM). In this work, we analysed AAR implemented via methionine restriction (MetR) in the MPC11 murine cell line and two human cell lines, KMS12-BM and L363. MetR exerted profound antiproliferative effects without causing cell death. In addition, methionine dependency was demonstrated in the cell lines investigated via homocysteine compensation. Additionally, mass spectrometry analyses of MPC11 cells revealed metabolic reprogramming, indicating that MetR led to a dramatic decrease in the (aerobic) glycolysis rate and in the abundances of energy equivalents and nucleotide synthesis metabolites. Taken together, the results of this study suggest that MetR is an important therapeutic option for MM.