Received for publication November 28, 2006.
Revised May 7, 2007.
Accepted for publication May 8, 2007.

CAFFEINE INHIBITS ADENOSINE-INDUCED ACCUMULATION OF HYPOXIA-INDUCIBLE FACTOR-1, VASCULAR ENDOTHELIAL GROWTH FACTOR AND INTERLEUKIN-8 EXPRESSION IN HYPOXIC HUMAN COLON CANCER CELLS

Abstract

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-1 protein accumulation in cancer cells. We show that HIF-1 and VEGF are increased through A₃ adenosine receptor stimulation, while the effects on IL-8 are mediated via the A_2B 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-1 accumulation, VEGF transcriptional activation and VEGF and IL-8 protein accumulation. Functionally, 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 analogue increased human umbilical vein endothelial cell (HUVEC) migration. These data provide evidence that adenosine could modulate the migration of colon cancer cells by a HIF-1/VEGF/IL-8-dependent mechanism and that caffeine has the potential to inhibit colon cancer cell growth.

Key words: Adenosine, Purinergic