Cysteine metabolic circuitries: druggable targets in cancer

Abstract

To enable survival in adverse conditions, cancer cells undergo global metabolic adaptations. The amino acid cysteine actively contributes to cancer metabolic remodelling on three different levels: first, in its free form, in redox control, as a component of the antioxidant glutathione or its involvement in protein s-cysteinylation, a reversible post-translational modification; second, as a substrate for the production of hydrogen sulphide (H2S), which feeds the mitochondrial electron transfer chain and mediates per-sulphidation of ATPase and glycolytic enzymes, thereby stimulating cellular bioenergetics; and, finally, as a carbon source for epigenetic regulation, biomass production and energy production. This review will provide a systematic portrayal of the role of cysteine in cancer biology as a source of carbon and sulphur atoms, the pivotal role of cysteine in different metabolic pathways and the importance of H2S as an energetic substrate and signalling molecule. The different pools of cysteine in the cell and within the body, and their putative use as prognostic cancer markers will be also addressed. Finally, we will discuss the pharmacological means and potential of targeting cysteine metabolism for the treatment of cancer.

Metabolic Reprogramming in Anticancer Drug Resistance: A Focus on Amino Acids

“…Cancer cells mainly depend on exogenous cysteine upregulating the system xc--mediated import of cystine in exchange for glutamate [141]. Serine is a primary feeder of one-carbon metabolism in cancer, sustaining purine and thymidylate biosynthesis.…”

The Harmonious Interplay of Amino Acid and Monocarboxylate Transporters Induces the Robustness of Cancer Cells

“…Neighboring stromal cells characterized by BMSCs can take up cystine via system Xc(-) and release cysteine [ 31 ]. A vast majority of cells, including tumor cells, do not depend on extracellular cysteine for GSH synthesis [ 31 , 35 , 36 ]. Instead, they take up cystine (two cysteine molecules joined by a disulfide bond), the more abundant and more stable oxidized form, and reduce it to cysteine in the cytoplasm [ 37 ].…”

Aryl Hydrocarbon Receptor and Cysteine Redox Dynamics Underlie (Mal)adaptive Mechanisms to Chronic Intermittent Hypoxia in Kidney Cortex

“…In fact, we have previously shown that CIH changes the dynamics of cysteine pool to an oxidative status in the kidney when HTN is established [ 7 ]. Cysteine (Cys) is the predominating thiol in extracellular fluids [ 12 , 13 ] and its availability is a net contribution of three pools which can dynamically exchange one-to-one depending on the redox status of the tissue involved [ 7 , 14 , 15 , 16 ]. The protein-bound fraction ( S -cysteinylated proteins, CysSSP) is generated by a reversible post-translational modification through a disulfide bond [ 14 ].…”