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Preclinical Studies and Early Drug Development: Predicting Tumor Response to Cytotoxic Therapy

Clusterin is induced by cancer chemotherapy and suppresses histone deacetylase inhibitor-induced apoptosis in breast cancer

University of Kentucky, Lexington, KY

Abstract

B22

Background: Solid tumors are frequently treated with a combination of chemotherapy, radiation, and surgery. Highly malignant, p53-negative cancer cells induce the expression of clusterin in response to chemotherapy and radiation, and clusterin suppresses apoptosis and promotes drug resistance. Clusterin binds to Bax and can also promote apoptosis by binding to Ku70 in the nucleus. We have found that histone deacetylases regulate clusterin stability after chemotherapy.Experimental procedures: MDA-MB-231 human breast cancer cells were treated with doxorubicin in combination with pharmacological histone deacetylase inhibitors (HDIs), and clusterin expression was analyzed by western blot. Clusterin expression was then suppressed by RNAi, and its effect on apoptosis was analyzed by cleavage of PARP and pro-caspase 3.Results: Clusterin expression was induced by doxorubicin, and clusterin was hyper-expressed 2.4-fold following combined treatment with doxorubicin and the histone deacetylase inhibitors (HDIs) sodium butyrate or SAHA (suberoylanilide hydroxamic acid), suggesting that clusterin is inhibited by histone deacetylases. However, HDIs had a modest effect on clusterin transcription, suggesting that HDIs increase the post-transcriptional stability of clusterin. Clusterin was hyper-expressed following treatment with HDIs combined with etoposide or camptothecin, indicating that hyper-expression is not specific to doxorubicin, and doxorubicin/HDI treatment led to clusterin hyper-expression in multiple breast cancer cell lines. Using RNAi directed to clusterin, we determined that clusterin suppressed HDI-induced apoptosis. Clusterin suppressed polyADP ribose polymerase (PARP) cleavage, cytochrome c release, and caspase 3 activity (P<0.001). Surprisingly, clusterin had a diminished anti-apoptotic activity following treatment with doxorubicin and HDIs, suggesting that doxorubicin alters the anti-apoptotic function of clusterin in response to HDIs.Conclusions: Histone deacetylase inhibitors (HDIs) are a promising class of anti-neoplastic agents, and clusterin is a candidate resistance protein for HDIs. Agents that inhibit clusterin are undergoing clinical trials in prostate and lung cancer, and we propose that these agents may be effective in combination with HDIs. However, we have also demonstrated that clusterin suppresses apoptosis in HDI-chemotherapy combinations, suggesting that clusterin induction may be an important determinant in selecting specific treatment regimens for the individualized treatment of cancer.