The anti-apoptotic protein Mcl-1 is overexpressed in prostate cancer

Abstract

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Therapy escape and progression of prostate cancer is associated with enhanced survival signals and resistance to induction of apoptosis (programmed cell death). Mcl-1 (myeloid cell lymphoma 1) is an anti-apoptotic protein of the Bcl-2 family, which functions in the regulation of apoptosis. We investigated its role in prostate cancer, employing measurement of expression in tumor specimens and regulation of expression in the LNCaP prostate cancer progression model. The androgen-sensitive prostate cancer prostate LNCaP and its long-term androgen ablated sublines LNCaP-abl and LNCaP-abl HOF - the latter two representing advanced prostate cancer - were used to analyze regulation of expression of Mcl-1 and the inpact on induction of apoptosis. Expression levels in the different stages of prostate cancer were determined by immunohistochemistry. Tissue specimens were obtained from prostate cancer patients undergoing radical prostatectomy, from palliative transurethral resections performed after development of hormone-resistant tumors and from distant metastasis removed surgically for palliative reasons. Simulation of long-term androgen ablation therapy in cell culture using LNCaP cells results in upregulation of MCl-1 expression. Regulation of expression involves the protein kinase B (PKB) survival pathway. Mcl-1 levels decrease after inhibition of PKB in LNCaP cell. Most interestingly this downregulation is not seen in the long-term androgen ablated LNCaP-abl cells. Mcl-1 is rarely expressed in benign epithelium, however, in the fast majority of prostate tumors. Immunohistochemistry revealed expression in only 1 of 14 benign specimens, but 59 of 67(88%) primary tumors, in all of 24 local recurrent tumors, in all of 11 lymph node metastases and in 7 of 8 bone metastases specimens. Comparison of non-malignant primary epithelial prostate cells with metastatic cancer cell lines confirmed an increase of Mcl-1 expression in the tumor cells.In conclusion, Mcl-1 overexpression is an early event in prostate cancer suggesting it as a potential target for tumor therapy. This is accompanied by dysregulation of expression during progression. It will be important to understand the interplay of Mcl-1 with the other proteins that regulate the induction of apoptosis.