Poster Presentation 25th Lorne Cancer Conference 2013

Mechanisms underlying prostate cancer cell death induced by combinatorial treatment with an HDAC inhibitor and an antiandrogen (#136)

Sarah Carter 1 , Margaret Centenera 1 , Wayne Tilley 1 , Luke Selth 1 , Lisa Butler 1 2
  1. Dame Roma Mitchell Cancer Research Laboratories and Adelaide Prostate Cancer Research Centre, University of Adelaide and Hanson Institute, Adelaide, SA, Australia
  2. Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia

Prostate cancer cells rely on androgen receptor (AR) signalling for growth and survival, and this dependence is exploited for treatment of metastatic prostate cancer by inhibition or reduction of available androgen in the patient. This treatment ultimately fails, and we propose that more effective inhibition of AR signalling through combinatorial strategies may improve patient outcomes. Histone deacetylase inhibitors (HDACIs) and AR antagonists are two distinct classes of clinical agents that are known to modulate levels and/or activity of the AR. We have shown that the combination of vorinostat, a HDACI, and bicalutamide, an AR antagonist, significantly enhances death of prostate cancer cells. In this study, we investigated whether this combination relies solely on enhanced androgen blockade for its apoptotic effect, or if a unique mechanism is responsible. LNCaP human prostate cancer cells were treated with bicalutamide and vorinostat, alone or in combination, and RNA was analysed on Affymetrix Human Genechip Gene 1.0 ST Arrays. Analysis of the resulting gene profiles showed that a substantial number of the genes modulated by the combination were androgen regulated, however, qRT-PCR validation of a subset of these genes showed that the combination did not further alter their expression over bicalutamide alone. This indicated that the combination mechanism of action may not be completely explained by enhanced androgen blockade. Further pathway analysis implicated NFKBIA loss, leading to deregulation of NF-κB and p53 signalling, as a potential mechanism. Specific knockdown of NFKBIA resulted in significant cell death similar in magnitude to that observed with combination treatment, implicating NFKBIA as a key regulator of prostate cancer cell survival. Taken together, our data suggest that while the combination of vorinostat and bicalutamide blocks androgen signalling in prostate cancer cells, it also causes deregulation of NF-κB and p53 signalling which may mediate cell death induced by this treatment.