Comprehensive Metabolic Tracing Reveals the Origin and Catabolism of Cysteine in Mammalian Tissues and Tumors

Abstract

Cysteine plays critical roles in cellular biosynthesis, enzyme catalysis, and redox metabolism. The intracellular cysteine pool can be sustained by cystine uptake or de novo synthesis from serine and homocysteine. Demand for cysteine is increased during tumorigenesis for generating glutathione to deal with oxidative stress. While cultured cells have been shown to be highly dependent on exogenous cystine for proliferation and survival, how diverse tissues obtain and use cysteine in vivo has not been characterized. We comprehensively interrogated cysteine metabolism in normal murine tissues and cancers that arise from them using stable isotope 13C1-serine and 13C6-cystine tracing. De novo cysteine synthesis was highest in normal liver and pancreas and absent in lung tissue, while cysteine synthesis was either inactive or downregulated during tumorigenesis. By contrast, cystine uptake and metabolism to downstream metabolites was a universal feature of normal tissues and tumors. However, differences in glutathione labeling from cysteine were evident across tumor types. Thus, cystine is a major contributor to the cysteine pool in tumors, and glutathione metabolism is differentially active across tumor types.

Plasma Metabolite Profiling in the Search for Early-Stage Biomarkers for Lung Cancer: Some Important Breakthroughs

“…In contrary to the increased acetate levels, decreased cysteine plasma levels are found in lung cancer. Cysteine is of great importance in energy production, cellular biosynthesis, enzyme catalysis, and redox metabolism [49]. During tumor development, there is an increased demand for cysteine to elevate glutathione production to protect cancer cells from death due to increased, accumulated oxidative stress levels.…”

“…During tumor development, there is an increased demand for cysteine to elevate glutathione production to protect cancer cells from death due to increased, accumulated oxidative stress levels. Cysteine is of utter importance, together with glycine and glutamate, for glutathione formation by glutamyl-cysteine ligase (GCL) [49]. Cysteine is transported into the cell using both the excitatory amino acid transporter 3 (EAAT3 / SCL1A1) and the alanine-serine-cysteine transporter 1 and 2 (ASCT1/2) [50].…”

“…Besides its role in ROS protection, cysteine is also used as a carbon source during energy production by contributing to the TCA cycle after its conversion to pyruvate or α-ketoglutarate [52]. Even though many cancer types show an increase in de novo synthesis of cysteine, lung cancer cells show an inactivated pathway during tumorigenesis [49]. Despite the inactivation of cysteine synthesis, cysteine uptake and metabolism remain.…”

Plasma Metabolite Profiling in the Search for Early-Stage Biomarkers for Lung Cancer: Some Important Breakthroughs

“…Contrary to the increased acetate levels, decreased cysteine plasma levels are found in lung cancer. Cysteine is of great importance in energy production, cellular biosynthesis, enzyme catalysis, and redox metabolism [52]. During tumor development, there is an increased demand for cysteine to elevate glutathione production to protect cancer cells from death due to increased, accumulated oxidative stress levels.…”

“…During tumor development, there is an increased demand for cysteine to elevate glutathione production to protect cancer cells from death due to increased, accumulated oxidative stress levels. Cysteine is of great importance, together with glycine and glutamate, for glutathione formation by glutamyl-cysteine ligase (GCL) [52]. Cysteine is transported into the cell using both the excitatory amino acid transporter 3 (EAAT3/SCL1A1) and the alanine-serine-cysteine transporter 1 and 2 (ASCT1/2) [53].…”