PMID- 24681637
OWN - NLM
STAT- MEDLINE
DCOM- 20150122
LR  - 20231213
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 5
IP  - 6
DP  - 2014 Mar 30
TI  - Atg7- and Keap1-dependent autophagy protects breast cancer cell lines against 
      mitoquinone-induced oxidative stress.
PG  - 1526-37
AB  - The interplay between oxidative stress and autophagy is critical for determining 
      the fate of cancer cells exposed to redox-active and cytotoxic chemotherapeutic 
      agents. Mitoquinone (MitoQ), a mitochondrially-targeted redox-active ubiquinone 
      conjugate, selectively kills breast cancer cells over healthy mammary epithelial 
      cells. We reported previously that MitoQ, although a derivative of the 
      antioxidant ubiquinone, can generate excess ROS and trigger the Keap1-Nrf2 
      antioxidant response in the MDA-MB-231 cell line. Following MitoQ treatment, a 
      greater number of cells underwent autophagy than apoptosis. However, the 
      relationship between MitoQ-induced oxidative stress and autophagy as a primary 
      cellular response was unclear. In this report, we demonstrate that MitoQ induces 
      autophagy related gene 7 (Atg7)-dependent, yet Beclin-1-independent, autophagy 
      marked by an increase in LC3-II. Both the ATG7-deficient human MDA-MB-231 cells 
      and Atg7-knockout mouse embryonic fibroblasts exhibited lower levels of autophagy 
      following MitoQ treatment than their respective wild-type counterparts. Increased 
      apoptosis was confirmed in these autophagy-deficient isogenic cell line pairs, 
      indicating that autophagy was attempted for survival in wild type cell lines. 
      Furthermore, we observed higher levels of ROS in Atg7-deficient cells, as 
      measured by hydroethidine oxidation. In Atg7-deficient cells, redox-sensitive 
      Keap1 degradation was decreased, suggesting autophagy- and Atg7-dependent 
      degradation of Keap1. Conversely, downregulation of Keap1 decreased autophagy 
      levels, increased Nrf2 activation, upregulated cytoprotective antioxidant gene 
      expression, and caused accumulation of p62, suggesting a feedback loop between 
      ROS-regulated Keap1-Nrf2 and Atg7-regulated autophagy. Our data indicate that 
      excessive ROS causes the upregulation of autophagy, and autophagy acts as an 
      antioxidant feedback response triggered by cytotoxic levels of MitoQ.
FAU - Gonzalez, Yanira
AU  - Gonzalez Y
AD  - Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food 
      and Drug Administration.
FAU - Aryal, Baikuntha
AU  - Aryal B
FAU - Chehab, Leena
AU  - Chehab L
FAU - Rao, V Ashutosh
AU  - Rao VA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BECN1 protein, human)
RN  - 0 (Beclin-1)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (Membrane Proteins)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Organophosphorus Compounds)
RN  - 0 (RNA, Messenger)
RN  - 1339-63-5 (Ubiquinone)
RN  - 47BYS17IY0 (mitoquinone)
RN  - EC 6.2.1.45 (ATG7 protein, human)
RN  - EC 6.2.1.45 (Autophagy-Related Protein 7)
RN  - EC 6.2.1.45 (Ubiquitin-Activating Enzymes)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Apoptosis Regulatory Proteins/antagonists & inhibitors/genetics/metabolism
MH  - Autophagy/*drug effects
MH  - Autophagy-Related Protein 7
MH  - Beclin-1
MH  - Blotting, Western
MH  - Breast Neoplasms/*drug therapy/metabolism/*pathology
MH  - Cell Proliferation/drug effects
MH  - Female
MH  - Humans
MH  - Immunoenzyme Techniques
MH  - Intracellular Signaling Peptides and Proteins/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Kelch-Like ECH-Associated Protein 1
MH  - Membrane Proteins/antagonists & inhibitors/genetics/metabolism
MH  - Mice
MH  - NF-E2-Related Factor 2/genetics/metabolism
MH  - Organophosphorus Compounds/*pharmacology
MH  - Oxidative Stress/*drug effects
MH  - RNA, Messenger/genetics
MH  - Real-Time Polymerase Chain Reaction
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Tumor Cells, Cultured
MH  - Ubiquinone/*analogs & derivatives/pharmacology
MH  - Ubiquitin-Activating Enzymes/antagonists & inhibitors/genetics/*metabolism
PMC - PMC4039229
EDAT- 2014/04/01 06:00
MHDA- 2015/01/23 06:00
PMCR- 2014/03/01
CRDT- 2014/04/01 06:00
PHST- 2014/04/01 06:00 [entrez]
PHST- 2014/04/01 06:00 [pubmed]
PHST- 2015/01/23 06:00 [medline]
PHST- 2014/03/01 00:00 [pmc-release]
AID - 1715 [pii]
AID - 10.18632/oncotarget.1715 [doi]
PST - ppublish
SO  - Oncotarget. 2014 Mar 30;5(6):1526-37. doi: 10.18632/oncotarget.1715.