PMID- 18240292
OWN - NLM
STAT- MEDLINE
DCOM- 20080904
LR  - 20220409
IS  - 1098-2744 (Electronic)
IS  - 0899-1987 (Linking)
VI  - 47
IP  - 9
DP  - 2008 Sep
TI  - Inhibition of HIF-1 alpha and VEGF expression by the chemopreventive bioflavonoid 
      apigenin is accompanied by Akt inhibition in human prostate carcinoma PC3-M 
      cells.
PG  - 686-700
LID - 10.1002/mc.20421 [doi]
AB  - Progression of cancer leads to hypoxic solid tumors that mount specific cell 
      signaling responses to low oxygen conditions. An important objective of 
      anti-cancer therapy is the development of new drugs that suppress hypoxic 
      responses in solid tumors. Apigenin is a natural flavone that has been shown to 
      have chemopreventive and/or anti-cancer properties against a number of tumor 
      types. However, the mechanisms underlying apigenin's chemopreventive properties 
      are not yet completely understood. In this study, we have investigated the 
      effects of apigenin on expression of hypoxia-inducible factor-1 (HIF-1) in human 
      metastatic prostate PC3-M cancer cells. We found that hypoxia induced a 
      time-dependent increase in the level of HIF-1alpha subunit protein in PC3-M 
      cells, and treatment with apigenin markedly decreased HIF-1alpha expression under 
      both normoxic and hypoxic conditions. Further, apigenin prevented the activation 
      of the HIF-1 downstream target gene vascular endothelial growth factor (VEGF). We 
      then showed that apigenin inhibited expression of HIF-1alpha by reducing 
      stability of the protein as well as by reducing the level of HIF-1alpha mRNA. We 
      also found that apigenin inhibited Akt and GSK-3beta phosphorylation in PC3-M 
      cells. Further experiments demonstrated that constitutively active Akt blunted 
      the effect of apigenin on HIF-1alpha expression. Taken together, our results 
      identify apigenin as a bioflavonoid that inhibits hypoxia-activated pathways 
      linked to cancer progression in human prostate cancer, in particular the 
      PI3K/Akt/GSK-3 pathway. Further studies on the mechanism of action of apigenin 
      will likely provide new insight into its applicability for pharmacologic 
      targeting of HIF-1alpha for cancer therapeutic or chemopreventive purposes.
FAU - Mirzoeva, Salida
AU  - Mirzoeva S
AD  - Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, 
      Northwestern University, Chicago, Illinois 60611, USA.
FAU - Kim, Nam Deuk
AU  - Kim ND
FAU - Chiu, Karen
AU  - Chiu K
FAU - Franzen, Carrie A
AU  - Franzen CA
FAU - Bergan, Raymond C
AU  - Bergan RC
FAU - Pelling, Jill C
AU  - Pelling JC
LA  - eng
GR  - P50 CA90386/CA/NCI NIH HHS/United States
GR  - T32-0700085/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Carcinog
JT  - Molecular carcinogenesis
JID - 8811105
RN  - 0 (Flavonoids)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 7V515PI7F6 (Apigenin)
SB  - IM
MH  - Apigenin/*pharmacology
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Flavonoids/*pharmacology
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors/*genetics
MH  - Male
MH  - Neoplasm Metastasis
MH  - Prostatic Neoplasms/*pathology
MH  - Vascular Endothelial Growth Factor A/antagonists & inhibitors/*genetics
EDAT- 2008/02/02 09:00
MHDA- 2008/09/05 09:00
CRDT- 2008/02/02 09:00
PHST- 2008/02/02 09:00 [pubmed]
PHST- 2008/09/05 09:00 [medline]
PHST- 2008/02/02 09:00 [entrez]
AID - 10.1002/mc.20421 [doi]
PST - ppublish
SO  - Mol Carcinog. 2008 Sep;47(9):686-700. doi: 10.1002/mc.20421.