Multiple pathways regulating the anti-apoptotic protein clusterin in breast cancer

Melissa K. Ranney, Ikhlas S.A. Ahmed, Kelly R. Potts, Rolf J. Craven

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Cancer chemotherapy inhibits tumor growth, in part, by triggering apoptosis, and anti-apoptotic proteins reduce the effectiveness of chemotherapy. Clusterin, a chaperone-like protein that binds to apoptotic and DNA repair proteins, is induced by chemotherapy and promotes tumor cell survival. Histone deacetylase inhibitors (HDIs) such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) are pharmacological agents that induce differentiation and apoptosis in cancer cells by altering chromatin structure, and we have found that combinations of chemotherapeutic drugs such as doxorubicin and HDIs efficiently induce apoptosis, even though they paradoxically induce high levels of clusterin. The hyper-expressed form of clusterin localizes to mitochondria, inhibits cytochrome c release, and is inhibited by the proteasome. When HDIs are used as single agents, clusterin suppresses cytochrome c release and apoptosis. However, doxorubicin/HDI-induced apoptosis is not inhibited by clusterin, and clusterin-resistant apoptosis corresponds with markers of the extrinsic/receptor-mediated apoptotic pathway. Thus, chemotherapy-HDI combinations are capable of overcoming an innate anti-apoptotic pathway of tumor cells, suggesting that chemotherapy-HDI combinations have potential for treating advanced stage breast cancer.

Original languageEnglish
Pages (from-to)1103-1111
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number9
StatePublished - Sep 2007

Bibliographical note

Funding Information:
We are grateful to the advice and encouragement of our colleague, Dr. Steve Zimmer, who passed away last June 2006. We are also grateful to colleagues in the Department of Molecular and Biomedical Pharmacology and to Rachel Chitti and Julia Craven for advice and helpful comments. This work was aided by grant #85-001-19-IRG from the American Cancer Society and by NIH COBRE P20 RR 15592.


  • Apoptosis
  • Breast cancer
  • Calpain
  • Caspase
  • Clusterin
  • Doxorubicin
  • Histone deacetylase
  • PARP
  • Proteasome

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


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