PMID- 17488804
OWN - NLM
STAT- MEDLINE
DCOM- 20070905
LR  - 20220331
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 72
IP  - 2
DP  - 2007 Aug
TI  - Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible 
      factor-1alpha, vascular endothelial growth factor, and interleukin-8 expression 
      in hypoxic human colon cancer cells.
PG  - 395-406
AB  - Frequent coffee consumption has been associated with a reduced risk of colorectal 
      cancer in a number of case-control studies. Coffee is a leading source of 
      methylxanthines, such as caffeine. The induction of vascular endothelial growth 
      factor (VEGF) and interleukin-8 (IL-8) is an essential feature of tumor 
      angiogenesis, and the hypoxia-inducible factor-1 (HIF-1) transcription factor is 
      known to be a key regulator of this process. In this study, we investigated the 
      effects of caffeine on HIF-1 protein accumulation and on VEGF and IL-8 expression 
      in the human colon cancer cell line HT29 under hypoxic conditions. Our results 
      show that caffeine significantly inhibits adenosine-induced HIF-1alpha protein 
      accumulation in cancer cells. We show that HIF-1alpha and VEGF are increased 
      through A3 adenosine receptor stimulation, whereas the effects on IL-8 are 
      mediated via the A2B subtype. Pretreatment of cells with caffeine significantly 
      reduces adenosine-induced VEGF promoter activity and VEGF and IL-8 expression. 
      The mechanism of caffeine seems to involve the inhibition of the extracellular 
      signal-regulated kinase 1/2 (ERK1/2), p38, and Akt, leading to a marked decrease 
      in adenosine-induced HIF-1alpha accumulation, VEGF transcriptional activation, 
      and VEGF and IL-8 protein accumulation. From a functional perspective, we observe 
      that caffeine also significantly inhibits the A3 receptor-stimulated cell 
      migration of colon cancer cells. Conditioned media prepared from colon cells 
      treated with an adenosine analog increased human umbilical vein endothelial cell 
      migration. These data provide evidence that adenosine could modulate the 
      migration of colon cancer cells by an HIF-1alpha/VEGF/IL-8-dependent mechanism 
      and that caffeine has the potential to inhibit colon cancer cell growth.
FAU - Merighi, Stefania
AU  - Merighi S
AD  - Department of Clinical and Experimental Medicine, Pharmacology Unit, University 
      of Ferrara, Ferrara, Italy.
FAU - Benini, Annalisa
AU  - Benini A
FAU - Mirandola, Prisco
AU  - Mirandola P
FAU - Gessi, Stefania
AU  - Gessi S
FAU - Varani, Katia
AU  - Varani K
FAU - Simioni, Carolina
AU  - Simioni C
FAU - Leung, Edward
AU  - Leung E
FAU - Maclennan, Stephen
AU  - Maclennan S
FAU - Baraldi, Pier Giovanni
AU  - Baraldi PG
FAU - Borea, Pier Andrea
AU  - Borea PA
LA  - eng
PT  - Journal Article
DEP - 20070508
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Interleukin-8)
RN  - 0 (Receptor, Adenosine A2B)
RN  - 0 (Receptor, Adenosine A3)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 3G6A5W338E (Caffeine)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - K72T3FS567 (Adenosine)
SB  - IM
MH  - Adenosine/*pharmacology
MH  - Caffeine/*pharmacology
MH  - *Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Colonic Neoplasms/*metabolism/pathology
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Interleukin-8/*metabolism
MH  - Phosphorylation
MH  - Promoter Regions, Genetic
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Receptor, Adenosine A2B/genetics
MH  - Receptor, Adenosine A3/genetics/physiology
MH  - Vascular Endothelial Growth Factor A/genetics/*metabolism
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
EDAT- 2007/05/10 09:00
MHDA- 2007/09/06 09:00
CRDT- 2007/05/10 09:00
PHST- 2007/05/10 09:00 [pubmed]
PHST- 2007/09/06 09:00 [medline]
PHST- 2007/05/10 09:00 [entrez]
AID - mol.106.032920 [pii]
AID - 10.1124/mol.106.032920 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2007 Aug;72(2):395-406. doi: 10.1124/mol.106.032920. Epub 2007 May 
      8.