Abstract
Tumor cells adapt their metabolism to meet the energetic and anabolic requirements of high proliferation and invasiveness. The metabolic addiction has motivated the development of therapies directed at individual biochemical nodes. However, currently there are few possibilities to target multiple enzymes in tumors simultaneously. Flavin-containing enzymes, ca. 100 proteins in humans, execute key biotransformations in mammalian cells. To expose metabolic addiction, we inactivated a substantial fraction of the flavoproteome in melanoma cells by restricting the supply of the FMN and FAD precursor riboflavin, the vitamin B2. Vitamin B2 deficiency affected stability of many polypeptides and thus resembled the chaperone HSP90 inhibition, the paradigmatic multiple-target approach. In support of this analogy, flavin-depleted proteins increasingly associated with a number of proteostasis network components, as identified by the mass spectrometry analysis of the FAD-free NQO1 aggregates. Proteome-wide analysis of the riboflavin-starved cells revealed a profound inactivation of the mevalonate pathway of cholesterol synthesis, which underlines the manifold cellular vulnerability created by the flavoproteome inactivation. Cell cycle-arrested tumor cells became highly sensitive to alkylating chemotherapy. Our data suggest that the flavoproteome is well suited to design synthetic lethality protocols combining proteostasis manipulation and metabolic reprogramming.
Highlights
The uncontrollable proliferation and invasiveness of malignantly transformed cells are related with high energetic and anabolic costs
Tumor cells reprogram the metabolism resulting in transformationspecific enzymatic patterns
B16 cells were transfected by electroporation in 400 μl intracellular buffer (135 mM KCl, 0.2 mM CaCl2, 2 mM MgCl2, 5 mM EGTA, 10 mM HEPES pH 7.5) freshly supplemented with 25% fetal bovine serum (FBS) at 250 V and 950 μF using GenePulser Xcell (Bio-Rad Laboratories, USA)
Summary
The uncontrollable proliferation and invasiveness of malignantly transformed cells are related with high energetic and anabolic costs. To meet these needs, tumor cells reprogram the metabolism resulting in transformationspecific enzymatic patterns. One of the distinct metabolic features of tumors, the aerobic glycolysis, was noticed long before the dawn of the oncogene-centric understanding of the tumorigenesis[1]. Metabolic as well as other therapeutic schemes in oncology face two difficulties inherent to tumors, namely, the heterogeneity and adaptability of transformed cells[5]. Combination of different substances has been proposed early on and used since in a hope of targeting different tumor sublcones and restricting their evolution more efficiently.
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