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In the cell, 90% of GSH is located in the cytoplasm, 1012% in the mitochondria, and a small percentage in the endoplasmic reticulum (ER) ( The -glutamatyl cycle or Meister cycle initially proposed in the 60s described the synthesis and breakdown of GSH, making it a strong cysteine donor in physiological and pathological conditions ( de novo synthesis of GSH by cancer cells occurs as follows: GSH is first exported from the cell of origin via transporters known as Multiresistance Drug Proteins (MRPs), which belongs to the ATP binding cassette (ABC)s transporter family and is well-known player in cancer resistance mechanisms ( via the proton-coupled oligopeptide transporter family member PEPT2 ( via a specific transporter remains unclear ( Besides ATF4, another transcription factor that regulates xCT expression is the nuclear factor erythroid 2-related factor 2 (NRF2) via the antioxidant response element (ARE) present in the promoter region of xCT gene ( 2+ )

KRAS -mutant cells can be particularly dependent on glutamine as a carbon source to fuel the TCA cycle and as a nitrogen source for nucleotide, hexosamine and nonessential amino acid (NEAA) biosynthesis (Toda et al., 2016)

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