Reductive stress in cancer: coming out of the shadows

NRF2 (Nuclear factor erythroid 2-related factor 2)

a transcription factor that upregulates the expression of key antioxidant enzymes

superoxide dismutases

enzymes that dismutate superoxide O₂^- to H₂O₂

glutathione peroxidases

enzymes that use glutathione as a reducing agent in reducing H₂O₂ to H₂O and O₂

peroxidases

enzymes that reduce peroxides

catalase

enzyme that converts H₂O₂ to H₂O and O₂

NADPH

electron donor, needed to power the antioxidant enzymes

KEAP1

a scaffold protein that binds to NRF2 and CUL3 targets NRF2 for ubiquitination, and thus degradation

E3 ubiquitin ligase

enzymes that tag proteins with ubiquitin, marking them for degradation

K1696

a potent and specific inhibitor of KEAP1–NRF2 interaction

anchorage-independent colony formation

the ability of cells to grow and divide when suspended in a soft, semi-solid medium as opposed to being attached to a surface

ALDH3A1

enzyme that oxidizes aldehydes, having a primary role in increasing NADH levels and sensitizing KEAP1-dependent cells to NRF2 activation

dehydrogenase

enzyme that catalyzes the redox reactions by transferring electrons

NADH

reducing agent that donates electrons to complex 1 of the electron transport chain, whose levels are increased by NRF2 activation and ALDH3A1 activity

sulfenic acid

R-SOH

sulfonic acid

-R-S(=O₂)-OH

glutathionylation

the addition of a glutathione through a disulfide bond

nitrosylation

the transfer of nitric oxide to cysteine residue

CUL2FEM1B

an e3 ubiquitin ligase complex formed by CUL2 and FEM1B

FNIP1

substrate of CUL2FEM1B

degron

amino acid sequences recognized by protein complexes like the e3 ubiquitin ligases and that signals it for degradation

metabolic shuttles

transport vital molecules across membranes

citrulline and ornithine

amino acids that replenish fumarate from arginine

acetylcarnitine

compound that transports fatty acids to mitochondria for breakdown

NADH shuttle

glycerol-3-phosphate

AMPK, adenosine monophosphate-activated protein kinase

regulates energy metabolism, senses energy status by monitoring AMP:ATP ratio. when AMP:ATP is high (energy low), ampk is phosphorylated and activated, causing it to turn off anabolic (energy-consuming) reactions and turn on catabolic (energy-releasing) reactions

mTORC1

protein complex that is master regulator of cell growth, promoting anabolic processes (protein, lipid, nucleotide synthesis) upon sensing of abundant nutrients, energy