CaV1.3 Ion channel expression and hormone therapy in prostate cancer

  • Niamh McKerr

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Prostate cancer (PCa) is an age-related, heterogeneous disease and the most common cancer in UK males. Early localised PCa is commonly treated with radiotherapy or surgery where recurrent tumours are treated with hormone therapy, such as androgen-deprivation therapy (ADT) and/or androgen receptor (AR) antagonists, e.g. Enzalutamide (ENZ). Castrate-resistant disease, where tumours become resistant to hormone therapy, is characterised by limited effective treatments and poor survival outcomes. The aberrant expression and function of ion channels in the oncology field has been increasingly recognised in genomic and laboratory studies in recent years. In PCa, it has been shown that the voltage-gated calcium channel CACNA1D gene, is upregulated in genomic analyses using clinical cancer biopsies. The aim of this study was to investigate the expression, function and localisation of CaV1.3 using in vitro PCa cell models and during hormone therapy by utilising a range of laboratory techniques. CaV1.3 was overexpressed in AR-positive PCa cells but appeared to be localised within subcellular compartments. Treatment of LNCaP cells with AR antagonist, Enzalutamide resulted in the re-localisation of CaV1.3 to the plasma membrane where calcium imaging techniques highlighted the presence of depolarisation-induced calcium responses in a subpopulation of cells. Nifedipine-induced inhibition of CaV1.3 in ENZ-treated LNCaP cells appeared to increase apoptosis, albeit not significantly, compared to ENZ treatment alone. Investigation of trafficking mechanisms of CaV1.3 showed that plasma membrane surface expression of these ion channels is enhanced in LNCaP cells following treatment with trafficking inhibitor, Brefeldin A and the histone deacetylase inhibitor, sodium butyrate. Overall, the results of this study show that CaV1.3 is relevant to AR-positive and androgen-sensitive PCa and is associated with neuroendocrine differentiation. ENZ treatment promotes CaV1.3 plasma membrane localisation and functional expression in PCa subpopulations which may be worth therapeutic exploration.
Date of AwardJul 2021
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsNorthern Ireland Department for the Economy
SupervisorKaren McCloskey (Supervisor) & Ian Mills (Supervisor)

Keywords

  • Prostate cancer
  • ion channels
  • hormone therapy
  • CaV1.3
  • calcium signalling

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