PMID- 25682865
OWN - NLM
STAT- MEDLINE
DCOM- 20160112
LR  - 20201209
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 6
IP  - 6
DP  - 2015 Feb 28
TI  - Autophagy through 4EBP1 and AMPK regulates oxidative stress-induced premature 
      senescence in auditory cells.
PG  - 3644-55
AB  - The aim of this study was to determine whether autophagy and AMPK contribute to 
      premature senescence in auditory cells. Incubating HEI-OC1 auditory cells with 5 
      mM H2O2 for 1 h induced senescence, as demonstrated by senescence-associated 
      beta-galactosidase (SA-beta-gal) staining. H2O2 treatment significantly delayed 
      population-doubling time, leaving cell viability unchanged. Furthermore, the 
      proportion of SA-beta-gal-positive cells significantly increased. Autophagy-related 
      protein expression increased, with Atg7 and LC3-II peaking 6 h and Lamp2 peaking 
      24 h after H2O2 treatment. The expression of these proteins decreased 48 h after 
      treatment. Transmission electron microscopy revealed lipofuscin and aggregates 
      within autolysosomes, which accumulated markedly in the cytoplasm of HEI-OC1 
      cells 48 h after treatment. Akt and P70S6 phosphorylation markedly decreased 
      after H2O2 treatment, but 4EBP1 phosphorylation significantly increased 48 h 
      after treatment. After RNAi-mediated knockdown (KD) of Atg7 and AMPK, 
      H2O2-treated cells displayed dense SA-beta-gal staining. Also, premature senescence 
      was significantly induced. These suggest that a negative feedback loop may exist 
      between autophagy and AMPK signaling pathways in HEI-OC1 cells. In our model, 
      oxidative stress-induced premature senescence occurred due to impaired autophagy 
      function through 4EBP1 phosphorylation. Our results also indicate that AMPK may 
      regulate premature senescence in auditory cells in an autophagy-dependent and 
      independent manner.
FAU - Tsuchihashi, Nana Akagi
AU  - Tsuchihashi NA
AD  - Department of Otorhinolaryngology, Head and Neck Surgery, Keio University, School 
      of Medicine, Tokyo 160-8582, Japan.
AD  - Department of Otorhinolaryngology, Head and Neck Surgery, Kyushu University, 
      School of Medicine, Fukuoka 812-0054, Japan.
FAU - Hayashi, Ken
AU  - Hayashi K
AD  - Department of Otorhinolaryngology, Head and Neck Surgery, Keio University, School 
      of Medicine, Tokyo 160-8582, Japan.
AD  - Department of Otorhinolaryngology, Kamio Memorial Hospital, Tokyo 101-0063, 
      Japan.
FAU - Dan, Katsuaki
AU  - Dan K
AD  - Collaborative Research Resources, Core Instrumentation Facility, Keio University, 
      Tokyo 160-8582, Japan.
FAU - Goto, Fumiyuki
AU  - Goto F
AD  - Department of Otorhinolaryngology, Head and Neck Surgery, Keio University, School 
      of Medicine, Tokyo 160-8582, Japan.
FAU - Nomura, Yasuyuki
AU  - Nomura Y
AD  - Department of Otorhinolaryngology-Head and Neck Surgery, Nihon University, School 
      of Medicine, Tokyo 173-8610, Japan.
FAU - Fujioka, Masato
AU  - Fujioka M
AD  - Department of Otorhinolaryngology, Head and Neck Surgery, Keio University, School 
      of Medicine, Tokyo 160-8582, Japan.
FAU - Kanzaki, Sho
AU  - Kanzaki S
AD  - Department of Otorhinolaryngology, Head and Neck Surgery, Keio University, School 
      of Medicine, Tokyo 160-8582, Japan.
FAU - Komune, Shizuo
AU  - Komune S
AD  - Department of Otorhinolaryngology, Head and Neck Surgery, Kyushu University, 
      School of Medicine, Fukuoka 812-0054, Japan.
FAU - Ogawa, Kaoru
AU  - Ogawa K
AD  - Department of Otorhinolaryngology, Head and Neck Surgery, Keio University, School 
      of Medicine, Tokyo 160-8582, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Eif4ebp1 protein, mouse)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Phosphoproteins)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - Autophagy/drug effects/physiology
MH  - Carrier Proteins/*metabolism
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - Cellular Senescence/drug effects/*physiology
MH  - Eukaryotic Initiation Factors
MH  - Gene Knockdown Techniques
MH  - Hair Cells, Auditory/*cytology/drug effects/*metabolism
MH  - Hydrogen Peroxide/pharmacology
MH  - Mice
MH  - Oxidative Stress/drug effects/physiology
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Signal Transduction
MH  - Transfection
PMC - PMC4414143
EDAT- 2015/02/17 06:00
MHDA- 2016/01/13 06:00
PMCR- 2015/02/01
CRDT- 2015/02/17 06:00
PHST- 2014/11/17 00:00 [received]
PHST- 2014/12/08 00:00 [accepted]
PHST- 2015/02/17 06:00 [entrez]
PHST- 2015/02/17 06:00 [pubmed]
PHST- 2016/01/13 06:00 [medline]
PHST- 2015/02/01 00:00 [pmc-release]
AID - 2874 [pii]
AID - 10.18632/oncotarget.2874 [doi]
PST - ppublish
SO  - Oncotarget. 2015 Feb 28;6(6):3644-55. doi: 10.18632/oncotarget.2874.