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Tumor Biology |
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
The expression of interleukin 8 (IL-8) by human ovarian cancer cells
correlates directly with disease progression, but the exact mechanism
of IL-8 induction is not clear. The extracellular pH in solid tumors is
generally acidic because of elevated acid production and impaired
clearance of acidic metabolic wastes. We determined whether acidic
conditions also regulate the expression of IL-8 in human ovarian cancer
cells. Culturing SKOV3 ip1 ovarian cancer cells in acidic medium (pH
6.6) significantly increased IL-8 mRNA (Northern blot) and protein
(ELISA). The acidosis-mediated transient increase in IL-8 expression
involved both transcriptional activation of the IL-8
gene and enhanced stability of the IL-8 mRNA. Detailed
functional analysis of the IL-8 promoter revealed that the sequence
between -133 and -98 bp relative to the transcription initiation site
was primarily responsible for IL-8 gene transcriptional
activation by acidosis. Point-mutated luciferase reporter studies
indicated that activator protein-1 (AP-1) and nuclear factor-
B
(NF-B)-like factor were responsible for acidic pH-induced
transcriptional activation of the IL-8 gene, and EMSA
demonstrated that both NF-B and AP-1 bound to these sites on the
IL-8 promoter. These results indicate that acidic pH activates NF-B
and AP-1 in human ovarian cancer cells and in doing so increases
IL-8 gene expression.
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