In the present review, we will describe in more details cysteine implication in cancer (patho)physiology from two aspects cysteine as a proteinogenic amino acid and cysteine as an amino acid involved in the GSH- and thus redox- homeostasis. Nutrient supply and redox balance are therefore intertwined and of great importance for anti-cancer treatment. GSH is a key non-enzymatic player in cellular antioxidant defense and is broadly implicated in tumor initiation, progression, metastasis, and resistance. One particularity of cysteine is its semi-essential nature and its implication in GSH homeostasis. The central role of amino acids in antioxidant defense is mainly due to the involvement of serine, glutamine/glutamate and cysteine, in glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) production ( 2, 3). Key signatures of cancer cells, due to their highly proliferative nature, are intensified metabolic rate, increased oxidative pressure, and consequently, reliance on antioxidant defense in term of redox homeostasis maintenance. Since the early 20th century, the reprogramming of cellular metabolism has been recognized as one of the major hallmarks of oncogenesis ( 1) that has great potential for anti-cancer treatment. 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. 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. 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.

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. 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. The reliance of tumor metabolism on amino acids, especially amino acid transport systems, has been extensively studied over the past decade. Consequently, cancer cells rely on antioxidant defenses to overcome the associated increased production of reactive oxygen species (ROS). Lacassagne, Université Côte d'Azur, Nice, FranceĬancer cells are characterized as highly proliferative at the expense of enhancement of metabolic rate. 2Institute for Research on Cancer and Aging (IRCAN), CNRS, INSERM, Centre A.1Medical Biology Department, Centre Scientifique de Monaco (CSM), Monaco, Monaco.Boutaina Daher 1 *, Milica Vučetić 1 and Jacques Pouysségur 1,2 *

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