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Discovery of Differentially Expressed Genes Associated with Paclitaxel Resistance Using cDNA Array Technology: Analysis of Interleukin (IL) 6, IL-8, and Monocyte Chemotactic Protein 1 in the Paclitaxel-resistant Phenotype¹

Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114

In an attempt to define the molecular changes associated with the paclitaxel-resistant phenotype in human cancer, a paclitaxel-resistant ovarian cancer cell line, SKOV-3_TR, was established through stepwise selection in increasing paclitaxel concentrations. SKOV-3_TR was cross- resistant to doxorubicin and vincristine and overexpressed multidrug resistancegene 1 but not multidrug resistance associated protein. SKOV-3_TR and the paclitaxel-sensitive SKOV-3 parent line were characterized using human cDNA array technology that examined expression of a wide variety of genes involved in cell growth, signal transduction, cell death, and immune function. cDNA probes from reverse transcribed mRNAs of both paclitaxel-resistant and parent cells were compared to identify genes differentially expressed in the paclitaxel-resistant cells. Of 588 different human cDNA transcripts compared, 6 genes were found to be markedly decreased, and 12 genes increased in the resistant subline. Northern analysis and/or reverse transcription-PCR confirmed that 12 of these 18 genes were over- or underexpressed in SKOV-3_TR. In addition, at least eight of the genes were found differentially expressed in several other paclitaxel- and/or doxorubicin-resistant cell lines, both those with increased multidrug resistance expression and those without. Included in the set of overexpressed genes were the cytokines/chemokines interleukin 6, interleukin 8, and monocyte chemotactic protein 1. ELISA assays confirm that mRNA overexpression of these cytokine/chemokines was associated with the increased secretion of these molecules in the tissue culture supernatant. Evaluation of supernatants from an expanded collection of paclitaxel- and Adriamycin-resistant cell lines demonstrated that all of the resistant lines had significant overexpression of at least one cytokine/chemokine as compared with their drug-sensitive parent line. The overexpression of these cytokines seemed to be stable and associated with a drug-resistant phenotype with only a modest induction of cytokine expression in the parent line with short-term paclitaxel exposure. These findings suggest that the development of paclitaxel resistance is accompanied by multiple changes in gene expression including stable alterations in selective chemokine and cytokine expression. The role these associated genetic changes have in the drug-resistant phenotype is discussed.

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