ABSTRACT
Taxol (paclitaxel) is one of the most successful chemotherapeutic drugs in the treatment of human cancer. It has recently been questioned whether the mechanism of action in mitotic arrest, which is ubiquitously present in all cells, is sufficient to explain the tumor specificity, clinical efficacy, and side effects of taxol. In this report, we have identified a new protein target of taxol as GT198 (gene symbol PSMC3IP, also known as Hop2). GT198 is an oncoprotein and a DNA repair factor involved in human common solid tumors. The GT198 gene carries germline mutations in breast and ovarian cancer families and recurrent somatic mutations in tumor microenvironment. Mutant GT198 was identified in pericyte stem cells on capillary blood vessels inducing tumor angiogenesis. GT198 is a DNA-binding protein dimer, also stimulates DNA repair, regulates meiosis, participates in homologous DNA recombination, and activates nuclear receptor-mediated gene expression. Here we show that taxol directly binds to the DNA-binding domain of GT198 in vitro. Taxol serves as an allosteric inhibitor to block DNA binding to GT198 with an IC50 of 8.6 nM. Labeled taxol colocalizes with GT198 in interphase nuclei of cultured cells. Decreased GT198 expression desensitizes taxolinduced cell death, and taxol inhibits GT198 nuclear foci formation during DNA repair. Together, these results demonstrate that GT198 is a previously unrecognized direct protein target of taxol. The finding of taxol target as an oncoprotein GT198 in common solid tumors provides a rationale for the clinical efficacy of taxol. We anticipate that GT198 may serve as a clinical predictive marker of taxol efficacy as well as a new drug target for future anti-cancer therapy.
