Multiple pathways regulating the anti-apoptotic protein clusterin in breast cancer.
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.
Ranney
Melissa K
MK
Department of Molecular and Biomedical Pharmacology, Markey Cancer Center, University of Kentucky, MS-305 UKMC, Lexington, KY 40536, USA.
Ahmed
Ikhlas S A
IS
Potts
Kelly R
KR
Craven
Rolf J
RJ
D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D051152:Clusterin / Q000235:genetics* / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; C495242:CLU protein, human; D051152:Clusterin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D045304:Cytochromes c
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