Optimal debulking followed by chemotherapy is the standard treatment of managing late-stage ovarian cancer, but
chemoresistance is still a major problem. In this study, we compared expression profiles of primary tumor tissue
from five long-term (>8 years) and five short-term (<2 years) ovarian cancer survivors and identified clusterin as
one of the genes that were significantly up-regulated in short-term survivors. We then evaluated the prognostic
significance of clusterin and its possible correlation with chemoresistance in ovarian cancer by immunohistostaining
of clusterin in 62 tumor samples from patients with stage III, high-grade serous ovarian cancer. After adjusting
for debulking status and age, Cox regression analyses showed that high levels of clusterin expression correlate with
poor survival (hazard ratio, 1.07; 95% confidence interval, 1.002–1.443; P = .04). We also investigated clusterin in
paclitaxel resistance by modulating the endogenous clusterin expression in ovarian cancer cells and treating the cells
with purified clusterin. Results indicate that high-clusterin–expressing ovarian cancer cells are more resistant to paclitaxel.
Moreover, exposing ovarian cancer cells to exogenous clusterin increases cells’ resistance to paclitaxel. Finally,
using size exclusion chromatography and fluorescently labeled paclitaxel, we demonstrated that clusterin binds
to paclitaxel. In summary, our findings suggest that high levels of clusterin expression increase paclitaxel resistance
in ovarian cancer cells by physically binding to paclitaxel, which may prevent paclitaxel from interacting with microtubules
to induce apoptosis. Thus, clusterin is a potential therapeutic target for enhancing chemoresponsiveness in
patients with a high-level clusterin expression.