Abstract
BackgroundBIRC6 is a member of the Inhibitors of Apoptosis Protein (IAP) family which is thought to protect a variety of cancer cells from apoptosis. The main objective of the present study was to investigate whether BIRC6 plays a role in prostate cancer and could be useful as a novel therapeutic target.MethodsBIRC6 expression in cell lines was assessed using Western blot analysis and in clinical samples using immunohistochemistry of tissue microarrays. The biological significance of BIRC6 was determined by siRNA-induced reduction of BIRC6 expression in LNCaP cells followed by functional assays.ResultsElevated BIRC6 protein expression was found in prostate cancer cell lines and clinical specimens as distinct from their benign counterparts. Increased BIRC6 expression was associated with Gleason 6–8 cancers and castration resistance. Reduction of BIRC6 expression in LNCaP cells led to a marked reduction in cell proliferation which was associated with an increase in apoptosis and a decrease in autophagosome formation. Doxorubicin-induced apoptosis was found to be coupled to a reduction in BIRC6 protein expression.ConclusionThe data suggest a role for BIRC6 in prostate cancer progression and treatment resistance, and indicate for the first time that the BIRC6 gene and its product are potentially valuable targets for treatment of prostate cancers.
Highlights
Prostate cancers usually present as androgen-dependent tumors, susceptible to growth arrest/apoptosis induced by androgen ablation therapy [1]
Only low levels of BIRC6 protein expression were detected in BPH1 and RWPE1 benign prostate cell lines
The low intensity of expression observed in Gleason score 9–10 prostate cancer tissues was reflective of the large proportion of typically weak BIRC6expressing Gleason grade 5 cancers found in this group
Summary
Prostate cancers usually present as androgen-dependent tumors, susceptible to growth arrest/apoptosis induced by androgen ablation therapy [1]. Androgen ablation frequently leads to the development of castration-resistant (androgen-independent) prostate cancer, which is generally resistant to other available treatments. Development of castration-resistant prostate cancer is characteristically associated with marked increases in resistance to apoptosis, a major death pathway for drug action [1,2,3]. Apoptosis resistance resulting from up-regulation of antiapoptotic genes and their products is thought to be a key contributor in the development of castration resistance, as well as general resistance to anti-cancer treatments. Elucidating the role of anti-apoptotic genes/proteins in the progression of prostate cancer is likely to lead to improvements in the treatment of refractory disease. The main objective of the present study was to investigate whether BIRC6 plays a role in prostate cancer and could be useful as a novel therapeutic target
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