Whole-genome studies identify solute carrier transporters in cellular susceptibility to paclitaxel.

ABSTRACT

OBJECTIVE: The clinical use of paclitaxel is limited by variable responses and the potential for significant toxicity. To date, studies of associations between variants in candidate genes and paclitaxel effects have yielded conflicting results. We aimed to evaluate the relationships between global gene expression and paclitaxel sensitivity. METHODS: We utilized well-genotyped lymphoblastoid cell lines derived from the International HapMap Project to evaluate the relationships between cellular susceptibility to paclitaxel and global gene expression. Cells were exposed to varying concentrations of paclitaxel to evaluate paclitaxel-induced cytotoxicity and apoptosis. Among the top genes, we identified solute carrier (SLC) genes associated with paclitaxel sensitivity and narrowed down the list to those that had single nucleotide polymorphisms associated with both the expression level of the SLC gene and also with paclitaxel sensitivity. We performed an independent validation in an independent set of cell lines and also conducted functional studies using RNA interference. RESULTS: Of all genes associated with paclitaxel-induced cytotoxicity at P less than 0.05 (1713 genes), there was a significant enrichment in SLC genes (31 genes). A subset of SLC genes, namely SLC31A2, SLC43A1, SLC35A5, and SLC41A2, was associated with paclitaxel sensitivity and had regulating single nucleotide polymorphisms that were also associated with paclitaxel-induced cytotoxicity. Multivariate modeling demonstrated that those four SLC genes together explained 20% of the observed variability in paclitaxel susceptibility. Using RNA interference, we demonstrated increased paclitaxel susceptibility with knockdown of three SLC genes, SLC31A2, SLC35A5, and SLC41A2. CONCLUSION: Our findings are novel and lend further support to the role of transporters, specifically solute carriers, in mediating cellular susceptibility to paclitaxel.