Cysteine Depletion, a Key Action to Challenge Cancer Cells to Ferroptotic Cell Death

Abstract

Cancer cells are characterized as highly proliferative at the expense of enhancement of metabolic rate. Consequently, cancer cells rely on antioxidant defenses to overcome the associated increased production of reactive oxygen species (ROS). The reliance of tumor metabolism on amino acids, especially amino acid transport systems, has been extensively studied over the past decade. Although cysteine is the least abundant amino acid in the cell, evidences described it as one of the most important amino acid for cell survival and growth. Regarding its multi-functionality as a nutrient, protein folding, and major component for redox balance due to its involvement in glutathione synthesis, disruption of cysteine homeostasis appears to be promising strategy for induction of cancer cell death. Ten years ago, ferroptosis, a new form of non-apoptotic cell death, has been described as a result of cysteine insufficiency leading to a collapse of intracellular glutathione level. In the present review, we summarized the metabolic networks involving the amino acid cysteine in cancer and ferroptosis and we focused on describing the recently discovered glutathione-independent pathway, a potential player in cancer ferroptosis resistance. Then, we discuss the implication of cysteine as key player in ferroptosis as a precursor for glutathione first, but also as metabolic precursor in glutathione-independent ferroptosis axis.

Together we stand, apart we fall: how cell-to-cell contact/interplay provides resistance to ferroptosis

“…44 ), thanks to the presence of ubiquinol, as a reducing agent, and ferroptosis-supressor protein 1 (FSP1), as its regenerating enzyme, in the membrane compartments of the cell 45,46 . Even more, some additional roles (besides involvement in GSH biosynthesis) of CySH have been suggested as important for the process of ferroptosis, such as its incorporation into Coenzyme A-precursor of ubiquinol, via pantothenate pathway 44,47 , as well as its role in protein folding and endoplasmic reticulum homeostasis 48,49 . Lastly, an important and frequently overlooked feature of the GPx4 enzyme is its broad substrate specificity.…”

Amino Acid Transporters as Targets for Cancer Therapy: Why, Where, When, and How

“…Some amino acids are conditionally essential, which indicates that the amino acid is required for specific metabolic activities, which outstrip the capacity of the cell to synthesize it. A well-known example is the glutamine addiction of cancer cells [ 7 ], but asparagine [ 8 ], arginine [ 9 ], and cysteine/cystine [ 10 , 11 ] can also be conditionally essential. While differentiated cells also acquire amino acids, it is important to realize that all cells efficiently recycle amino acids through lysosomal and proteasomal protein digestion [ 1 , 12 , 13 ].…”

“…For many years, the research community has focused on three transporters, namely ASCT2 (SLC1A5) [ 30 , 31 ], LAT1 (SLC7A5) [ 32 , 33 ], and xCT (SLC7A11) [ 11 ]. The main reason for the interest in ASCT2 and LAT1 is the upregulation of these two transporters in many cancer cells [ 31 , 34 ].…”

Epigenetic Regulation and Nonepigenetic Mechanisms of Ferroptosis Drive Emerging Nanotherapeutics in Tumor

“…Cystinase depletes cysteine, which works as a precursor to glutathione and as a precursor to metabolism in the glutathione-independent hypertrophic axis. Finally, cystinase depletion promotes ferroptosis [ 52 ]. Further research identified P53 4KR as the acetylation site of P53 lysine K98 in mice.…”