PMID- 9563654
OWN - NLM
STAT- MEDLINE
DCOM- 19980507
LR  - 20190720
IS  - 0304-3835 (Print)
IS  - 0304-3835 (Linking)
VI  - 126
IP  - 1
DP  - 1998 Apr 10
TI  - Hypoxia-induced apoptosis in human hepatocellular carcinoma cells: a possible 
      involvement of the 6-TG-sensitive protein kinase(s)-dependent signaling pathway.
PG  - 97-104
AB  - Apoptosis is a morphologically and biochemically distinct form of cell death 
      which can be triggered by a variety of extracellular agents both during normal 
      developments and in adult pathological states. However, the molecular mechanism 
      of apoptotic cell death due to hypoxia has not been clearly elucidated. In this 
      study, we investigated critical factors involved in hypoxia-induced apoptosis 
      using HepG2, a human hepatocellular carcinoma cell line, as an experimental 
      model. We found that 24 h of exposure of HepG2 cells to hypoxia induced 
      apoptosis, for which de novo protein synthesis was required. Apoptosis was 
      demonstrated by DNA fragmentation and terminal deoxynucleotidyl 
      transferase-mediated dUTP nick end labeling (TUNEL) assay. Hypoxia-induced 
      apoptosis was associated with a marked induction of c-jun and c-fos messenger 
      RNAs. Electromobility shift assay showed the increased DNA binding activity of 
      AP-1 during hypoxia, suggesting that AP-1 may be involved in the induction of 
      cell death by acting as a transcriptional regulator. A purine analogue, 
      6-thioguanine (6-TG), significantly blocked the induction of apoptosis by 
      hypoxia. Moreover, the inductive effect of hypoxia on c-jun expression was also 
      inhibited by 6-TG, whereas the levels of c-fos mRNA and its protein were rather 
      strongly increased. Iodoacetamide (IAA), a non-specific inhibitor of ICE family 
      proteases, also has an inhibitory effect on hypoxia-induced apoptosis. These 
      results suggest that the 6-TG-sensitive protein kinase(s)-dependent signaling 
      pathway may be involved in the apoptotic response of HepG2 cells exposed to 
      hypoxia by increasing the level of c-jun and c-fos and the activity of AP-1 
      and/or by activating ICE family protease(s).
FAU - Bae, S K
AU  - Bae SK
AD  - Department of Molecular Biology, Pusan National University, South Korea.
FAU - Baek, J H
AU  - Baek JH
FAU - Lee, Y M
AU  - Lee YM
FAU - Lee, O H
AU  - Lee OH
FAU - Kim, K W
AU  - Kim KW
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - EC 2.7.- (Protein Kinases)
SB  - IM
MH  - *Apoptosis
MH  - Carcinoma, Hepatocellular/*pathology
MH  - *Cell Hypoxia
MH  - DNA Fragmentation
MH  - Humans
MH  - Liver Neoplasms/*pathology
MH  - Protein Kinases/physiology
MH  - Signal Transduction
MH  - Tumor Cells, Cultured
EDAT- 1998/05/01 00:00
MHDA- 1998/05/01 00:01
CRDT- 1998/05/01 00:00
PHST- 1998/05/01 00:00 [pubmed]
PHST- 1998/05/01 00:01 [medline]
PHST- 1998/05/01 00:00 [entrez]
AID - S0304-3835(97)00538-7 [pii]
AID - 10.1016/s0304-3835(97)00538-7 [doi]
PST - ppublish
SO  - Cancer Lett. 1998 Apr 10;126(1):97-104. doi: 10.1016/s0304-3835(97)00538-7.