PMID- 20805228
OWN - NLM
STAT- MEDLINE
DCOM- 20101130
LR  - 20230815
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 45
DP  - 2010 Nov 5
TI  - The antioxidant transcription factor Nrf2 negatively regulates autophagy and 
      growth arrest induced by the anticancer redox agent mitoquinone.
PG  - 34447-59
LID - 10.1074/jbc.M110.133579 [doi]
AB  - Mitoquinone (MitoQ) is a synthetically modified, redox-active ubiquinone compound 
      that accumulates predominantly in mitochondria. We found that MitoQ is 30-fold 
      more cytotoxic to breast cancer cells than to healthy mammary cells. MitoQ 
      treatment led to irreversible inhibition of clonogenic growth of breast cancer 
      cells through a combination of autophagy and apoptotic cell death mechanisms. 
      Relatively limited cytotoxicity was seen with the parent ubiquinone coenzyme 
      Q(10.) Inhibition of cancer cell growth by MitoQ was associated with G(1)/S cell 
      cycle arrest and phosphorylation of the checkpoint kinases Chk1 and Chk2. The 
      possible role of oxidative stress in MitoQ activity was investigated by measuring 
      the products of hydroethidine oxidation. Increases in ethidium and 
      dihydroethidium levels, markers of one-electron oxidation of hydroethidine, were 
      observed at cytotoxic concentrations of MitoQ. Keap1, an oxidative stress sensor 
      protein that regulates the antioxidant transcription factor Nrf2, underwent 
      oxidation, degradation, and dissociation from Nrf2 in MitoQ-treated cells. Nrf2 
      protein levels, nuclear localization, and transcriptional activity also increased 
      following MitoQ treatment. Knockdown of Nrf2 caused a 2-fold increase in 
      autophagy and an increase in G(1) cell cycle arrest in response to MitoQ but had 
      no apparent effect on apoptosis. The Nrf2-regulated enzyme NQO1 is partly 
      responsible for controlling the level of autophagy. Keap1 and Nrf2 act as redox 
      sensors for oxidative perturbations that lead to autophagy. MitoQ and similar 
      compounds should be further evaluated for novel anticancer activity.
FAU - Rao, V Ashutosh
AU  - Rao VA
AD  - Laboratory of Biochemistry, Center for Drug Evaluation and Research, Food and 
      Drug Administration, Bethesda, Maryland 20892, USA. ashutosh.rao@fda.hhs.gov
FAU - Klein, Sarah R
AU  - Klein SR
FAU - Bonar, Spencer J
AU  - Bonar SJ
FAU - Zielonka, Jacek
AU  - Zielonka J
FAU - Mizuno, Naoko
AU  - Mizuno N
FAU - Dickey, Jennifer S
AU  - Dickey JS
FAU - Keller, Paul W
AU  - Keller PW
FAU - Joseph, Joy
AU  - Joseph J
FAU - Kalyanaraman, Balaraman
AU  - Kalyanaraman B
FAU - Shacter, Emily
AU  - Shacter E
LA  - eng
GR  - R01CA125112/CA/NCI NIH HHS/United States
GR  - R01 CA136799/CA/NCI NIH HHS/United States
GR  - R01 CA125112/CA/NCI NIH HHS/United States
GR  - R01CA136799/CA/NCI NIH HHS/United States
GR  - R01 CA152810/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100830
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cytotoxins)
RN  - 0 (Fluorescent Dyes)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Organophosphorus Compounds)
RN  - 0 (Phenanthridines)
RN  - 1339-63-5 (Ubiquinone)
RN  - 38483-26-0 (hydroethidine)
RN  - 47BYS17IY0 (mitoquinone)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.11 (Checkpoint Kinase 2)
RN  - EC 2.7.11.1 (CHEK1 protein, human)
RN  - EC 2.7.11.1 (CHEK2 protein, human)
RN  - EC 2.7.11.1 (Checkpoint Kinase 1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/*drug effects/genetics
MH  - Autophagy/*drug effects/genetics
MH  - Cell Line, Tumor
MH  - Checkpoint Kinase 1
MH  - Checkpoint Kinase 2
MH  - Cytotoxins/pharmacology
MH  - Fluorescent Dyes/pharmacology
MH  - G1 Phase/*drug effects/genetics
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/genetics/metabolism
MH  - Kelch-Like ECH-Associated Protein 1
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - Organophosphorus Compounds/*pharmacology
MH  - Oxidation-Reduction/drug effects
MH  - Oxidative Stress/drug effects/genetics
MH  - Phenanthridines/pharmacology
MH  - Protein Kinases/genetics/metabolism
MH  - Protein Serine-Threonine Kinases/genetics/metabolism
MH  - S Phase/drug effects/genetics
MH  - Ubiquinone/*pharmacology
PMC - PMC2966059
EDAT- 2010/09/02 06:00
MHDA- 2010/12/14 06:00
PMCR- 2011/11/05
CRDT- 2010/09/01 06:00
PHST- 2010/09/01 06:00 [entrez]
PHST- 2010/09/02 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
PHST- 2011/11/05 00:00 [pmc-release]
AID - S0021-9258(20)46985-6 [pii]
AID - M110.133579 [pii]
AID - 10.1074/jbc.M110.133579 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Nov 5;285(45):34447-59. doi: 10.1074/jbc.M110.133579. Epub 2010 
      Aug 30.