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Clusterin interacts with paclitaxel and confer paclitaxel resistance in ovarian cancer

Journal Article


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Abstract


  • 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.

Authors


  •   Park, Dong Choon (external author)
  •   Yeo, Seung Geun (external author)
  •   Mark R Wilson
  •   Yerbury, Justin J.
  •   Kwong, Joseph (external author)
  •   Welch, William R. (external author)
  •   Choi, Yang Kyu (external author)
  •   Birrer, Michael J. (external author)
  •   Mok, Samuel C. (external author)
  •   Wong, Kwong-Kwok (external author)

Publication Date


  • 2008

Citation


  • Park, D., Yeo, S., Wilson, M. R., Yerbury, J., Kwong, J., Welch, W. R., Choi, Y., Birrer, M. J., Mok, S. C. & Wong, K. (2008). Clusterin interacts with paclitaxel and confer paclitaxel resistance in ovarian cancer. Neoplasia, 10 (9), 964-972.

Scopus Eid


  • 2-s2.0-50949115551

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2010&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/967

Has Global Citation Frequency


Number Of Pages


  • 8

Start Page


  • 964

End Page


  • 972

Volume


  • 10

Issue


  • 9

Place Of Publication


  • United States

Abstract


  • 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.

Authors


  •   Park, Dong Choon (external author)
  •   Yeo, Seung Geun (external author)
  •   Mark R Wilson
  •   Yerbury, Justin J.
  •   Kwong, Joseph (external author)
  •   Welch, William R. (external author)
  •   Choi, Yang Kyu (external author)
  •   Birrer, Michael J. (external author)
  •   Mok, Samuel C. (external author)
  •   Wong, Kwong-Kwok (external author)

Publication Date


  • 2008

Citation


  • Park, D., Yeo, S., Wilson, M. R., Yerbury, J., Kwong, J., Welch, W. R., Choi, Y., Birrer, M. J., Mok, S. C. & Wong, K. (2008). Clusterin interacts with paclitaxel and confer paclitaxel resistance in ovarian cancer. Neoplasia, 10 (9), 964-972.

Scopus Eid


  • 2-s2.0-50949115551

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2010&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/967

Has Global Citation Frequency


Number Of Pages


  • 8

Start Page


  • 964

End Page


  • 972

Volume


  • 10

Issue


  • 9

Place Of Publication


  • United States