Altered calcium signalling in prostate cancer facilitates progression to castrate resistance
O'Reilly, DebbieORCID: 0000-0001-9405-7961
(2021)
Altered calcium signalling in prostate cancer facilitates progression to castrate resistance.
PhD thesis, Dublin City University.
Prostate cancer (PCa) carries a significant clinical burden worldwide with ~1.3-million new cases annually. It is the most frequently diagnosed cancer in Irish men, excluding non-cutaneous skin cancer, and is the third most common cause of cancer related deaths among this cohort. The most utilised treatment for advanced or metastatic PCa is androgen deprivation therapy (ADT). Although this treatment initially shrinks the tumour, treatment resistance develops after ~2 years. At this stage, the disease is called castrate resistant prostate cancer (CRPC) and is associated with mortality. Calcium signalling has been implicated in the malignant progression of many cancers, particularly PCa. Research demonstrates that the L-type voltage gated calcium channel CaV1.3 is significantly increased in PCa tissues compared to normal prostate epithelia. The aim of this study was to explore the role CaV1.3 plays in ADT resistance and determine its underlying tumour biology.
This research investigates the mechanism associated with CaV1.3 upregulation and the progression to CRPC. Using clinical, in vivo and in vitro models we reveal that CaV1.3 is enhanced by ADT, which correlates with higher Gleason score and shorter time to biochemical recurrence. Herein we uncover a novel mechanism through which upregulated CaV1.3 functions to increase calcium mobilisation by enhancing store operated calcium entry (SOCE). Increased calcium results in altered cellular signalling and stable expression of Hif-1α under hypoxic conditions, it also increases the expression of PCa markers such as androgen receptor. This facilitates cell viability under conditions of ADT and maintaines the proliferative ability of CRPC. Confirming that CaV1.3 has a direct involvement in PCa progression and signifying that CaV1.3 could be utilised as both a biomarker for treatment resistance and as a drug target to prevent disease progression.