PMID- 25075425
OWN - NLM
STAT- MEDLINE
DCOM- 20150209
LR  - 20211203
IS  - 1347-8648 (Electronic)
IS  - 1347-8613 (Linking)
VI  - 125
IP  - 2
DP  - 2014
TI  - 4',6-dihydroxy-4-methoxyisoaurone inhibits the HIF-1alpha pathway through inhibition 
      of Akt/mTOR/p70S6K/4E-BP1 phosphorylation.
PG  - 193-201
AB  - 4',6-Dihydroxy-4-methoxyisoaurone (ISOA) is an isoaurone compound isolated from 
      Trichosanthes kirilowii seeds, which was identified as an inhibitor of tumor 
      growth. However, the mechanism by which ISOA inhibits hypoxia-inducible factor-1 
      (HIF-1)-mediated tumor growth is not fully understood. We here demonstrated the 
      effect of ISOA on HIF-1 activation. ISOA showed a potent inhibitory activity 
      against HIF-1 activation induced by hypoxia in various human cancer cell lines. 
      This compound markedly decreased the hypoxia-induced accumulation of HIF-1a 
      protein dose-dependently, whereas it did not affect the expressions of HIF-1b and 
      topoisomerase-I (Topo-I). Further analysis revealed that the suppression of 
      HIF-1a accumulation by ISOA was closely correlated with strong dephosphorylation 
      of Akt, mammalian target of rapamycin (mTOR), and its effectors ribosomal protein 
      S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 
      (4E-BP1), a pathway known to regulate HIF-1a expression at the translational 
      level. Furthermore, ISOA prevented hypoxia-induced expression of HIF-1 target 
      genes and suppresses the invasiveness of tumor cells. Taken together, our results 
      suggested that ISOA is an effective inhibitor of HIF-1 through targeting 
      Akt/mTOR/p70S6K/4E-BP1 pathway, thereby, providing new perspectives into the 
      mechanism of its anticancer activity.
FAU - Mi, Chunliu
AU  - Mi C
FAU - Ma, Juan
AU  - Ma J
FAU - Shi, Hui
AU  - Shi H
FAU - Li, Jing
AU  - Li J
FAU - Wang, Fei
AU  - Wang F
FAU - Lee, Jung Joon
AU  - Lee JJ
FAU - Jin, Xuejun
AU  - Jin X
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Japan
TA  - J Pharmacol Sci
JT  - Journal of pharmacological sciences
JID - 101167001
RN  - 0 (4',6-dihydroxy-4-methoxyisoaurone)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Phosphoproteins)
RN  - 0 (Sesquiterpenes)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - *Antineoplastic Agents, Phytogenic
MH  - Cell Cycle Proteins
MH  - Cell Line, Tumor
MH  - Depression, Chemical
MH  - Dose-Response Relationship, Drug
MH  - Gene Expression/drug effects/genetics
MH  - Humans
MH  - Hypoxia/genetics/metabolism
MH  - Hypoxia-Inducible Factor 1/*antagonists & 
      inhibitors/genetics/*metabolism/*physiology
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Biosynthesis/genetics
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/*metabolism
MH  - Sesquiterpenes/isolation & purification/*pharmacology
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Trichosanthes/*chemistry
EDAT- 2014/07/31 06:00
MHDA- 2015/02/11 06:00
CRDT- 2014/07/31 06:00
PHST- 2014/07/31 06:00 [entrez]
PHST- 2014/07/31 06:00 [pubmed]
PHST- 2015/02/11 06:00 [medline]
AID - 10.1254/jphs.13273fp [doi]
PST - ppublish
SO  - J Pharmacol Sci. 2014;125(2):193-201. doi: 10.1254/jphs.13273fp.