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

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

doi:10.1016/j.bbadis.2007.06.004

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

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

Pharmacology and Nutritional Sciences

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

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 language	English
Pages (from-to)	1103-1111
Number of pages	9
Journal	Biochimica et Biophysica Acta - Molecular Basis of Disease
Volume	1772
Issue number	9
DOIs	https://doi.org/10.1016/j.bbadis.2007.06.004
State	Published - 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.

Keywords

Apoptosis
Breast cancer
Calpain
Caspase
Clusterin
Doxorubicin
Histone deacetylase
PARP
Proteasome

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbadis.2007.06.004

Cite this

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title = "Multiple pathways regulating the anti-apoptotic protein clusterin in breast cancer",

abstract = "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.",

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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.",

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AU - Potts, Kelly R.

AU - Craven, Rolf J.

N1 - 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.

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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