Clusterin is a critical downstream mediator of stress-induced YB-1 transactivation in prostate cancer

Masaki Shiota, Amina Zoubeidi, Masafumi Kumano, Eliana Beraldi, Seiji Naito, Colleen C. Nelson, Poul H.B. Sorensen, Martin E. Gleave

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)

Abstract

Clusterin is a stress-activated, cytoprotective chaperone that confers broad-spectrum treatment resistance in cancer. However, the molecular mechanisms mediating CLU transcription following anticancer treatment stress remain incompletely defined. We report that Y-box binding protein-1 (YB-1) directly binds to CLU promoter regions to transcriptionally regulate clusterin expression. In response to endoplasmic reticulum stress inducers, including paclitaxel, YB-1 is translocated to the nucleus to transactivate clusterin. Furthermore, higher levels of activated YB-1 and clusterin are seen in taxane-resistant, compared with parental, prostate cancer cells. Knockdown of either YB-1 or clusterin sensitized prostate cancer cells to paclitaxel, whereas their overexpression increased resistance to taxane. Clusterin overexpression rescued cells from increased paclitaxel induced apoptosis following YB-1 knockdown; in contrast, however, YB-1 over expression did not rescue cells from increased paclitaxel-induced apoptosis following clusterin knockdown. Collectively, these data indicate that YB-1 transactivation of clusterin in response to stress is a critical mediator of paclitaxel resistance in prostate cancer.

Original languageEnglish
Pages (from-to)1755-1766
Number of pages12
JournalMolecular Cancer Research
Volume9
Issue number12
DOIs
Publication statusPublished - Dec 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

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