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

NLRP1

protein that triggers inflammation upon cellular stress

CARD8

protein that acts as inflammasome sensor, detecting signs of infection and cellular damage

capase-1

protease that processes inflammatory cytokines, triggering pyroptosis

pyroptosis

inflammatory cell death triggered by infections, toxins, or cellular stress

thioredoxin

antioxidant protein that reduces oxidized proteins and scavenges ros, maintaining redox balance

NACHT-LRR region

protein domain of nlrp1, consisting of nacht domain (located in center of protein, binds and hydrolyzes atp) and leucine-rich repeat domain (located at c-terminus of protein, senses signals associated with damage, interacts with nacht in the absence of signals to inhibit protein)

dithiothreitol

compound that is a strong reducing agent, breaks disulfide bonds

FIIND domain

protein domain in clrp1 and card8 domains; in nlrp1, ct domain generated by cleavage is active part of inflammasome

JSH-23

inhibitor of nuclear factor kappa 3, a regulator of inflammation

glutathione disulfide (GSSG)

the oxidized form of glutathione

SoNar

molecule that becomes fluorescent upon binding NADH/NAD⁺

iNAP

molecule that becomes fluorescent upon binding NADPH/NADP⁺

high-throughput

the ability to process a large number of samples in a short amount of time

KP372-1

a compound that consumes NAD(P)H, generating oxidative stress

NQO1

a protective enzyme that helps detoxify reactive quinones and combat oxidative stress in the body

LbNOX

enzyme that oxidizes NADH to NAD⁺, increasing the NAD⁺/NADH ratio

TPNOX

enzyme engineered from lbnox that oxidizes NADPH

LOXCAT

fusion protein of lactate oxidase and catalase that converts lactate to pyruvate

NADH dehydrogenase

complex I of the ETC, transfers electrons from NADH to ubiquinone

NDI1

a yeast enzyme that oxidizes nadh to nad+ without generating proton-motive force

NDUFS2

core component of complex I

auxotrophic

being unable to synthesize a necessary organic compound

metformin

medication used to treat type 2 diabetes by inhibiting mitochondrial respiration

IACS-010759

an inhibitor of complex I, causing reductive stress as nadh is unable to be oxidized to nad+

therapeutic index

a measure of drug's relative safety, comparing concentration for therapeutic effect to concentration for toxicity

oligomycin

inhibitor of mitochondrial ATP synthase

rotenone

inhibitor of mitochondrial complex I

BAY 87-2243

inhibitor of oxidative phosphorylation by activating glycolytic enzymes and pyruvate dehydrogenase kinase, which inhibits conversion of pyruvate to acetyl-coA

ascorbic acid

vitamin c, an antioxidant

core-shell nanostructure

nanoparticle with inner core of one material and outer shell of another

CdTe quantum dots

cadmium-tellurium nanocrystals with fluorescent properties

hydropersulfides

reducing agents stronger than thiols

carcinoma

a type of cancer that begins in epithelial cells (form protective layers on internal and external surfaces)

triple-negative breast cancer

an aggressive type of breast cancer that lacks estrogen receptors, progesterone receptors, and her2 receptors (human epidermal growth factor receptor 2 receptors)

doxorubicin

a chemotherapy that disrupts topoisomerase activity

L-2 hydroxyglutarate

a metabolic byproduct of cellular respiration that is produced in high quantities under hypoxia