IDENTIFICATION OF TUMOR-SPECIFIC PACLITAXEL (TAXOL)-RESPONSIVE REGULATORY ELEMENTS IN THE INTERLEUKIN-8 PROMOTER

Paclitaxel (Taxol) is a novel chemotherapeutic drug that is effective against breast and ovarian cancers, Although the primary target of pac litaxel is microtubules, its efficacy exceeds that of conventional mic rotubule-disrupting agents, suggesting that it may have additional cel lular effects, Previously, we demonstrated that paclitaxel can induce interleukin-8 (IL-8) gene expression at the transcriptional level in s ubsets of human ovarian cancer lines. In this as well as the previous report, we present evidence that this ability is not linked to the lip opolysaccharide pathway of IL-8 gene induction, The present study iden tifies the cis-acting elements and trails-acting factors involved in t his induction by transfecting DNA constructs containing the 5'-flankin g region of the IL-8 gene linked to the chloramphenicol acetyltransfer ase reporter gene into paclitaxel-responsive and nonresponsive ovarian cancer cells (responsiveness refers to the IL-8 response). Paclitaxel only activated the IL-8 promoter in responsive cells, The AP-1 and NF -kappa B binding sites in the IL-8 promoter are required for activatio n by paclitaxel; in contrast, a C/EBP site required for IL-8 promoter activation in other cell types is not involved. Gel shift assays demon strate that paclitaxel causes a marked increase in protein binding to the NF-kappa B and AP-1 consensus binding sequences in the paclitaxel- responsive ovarian cells, but not the nonresponsive cells, The inducti on of NF-kappa B and AP-I binding is reduced by the addition of protei n kinase C inhibitors and cyclic AMP effector, respectively, These res ults demonstrate a molecular mechanism for cell-specific paclitaxel-in duced IL-8 gene expression which may have clinical relevance.