CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer

Androgen deprivation therapy (ADT) is the main treatment for advanced prostate cancer (PCa) but resistance results in progression to terminal castrate resistant PCa (CRPC), where there is an unmet therapeutic need. Aberrant intracellular calcium (Cai2+) is known to promote neoplastic transformation and treatment resistance. There is growing evidence that expression of voltage gated calcium channels (VGCC) is increased in cancer, particularly the CACNA1D /CaV1.3 in CRPC. The aim of this study was to investigate if increased CaV1.3 drives resistance to ADT and determine its associated impact on Cai2+ and cancer biology. Bioinformatic analysis revealed that CACNA1D gene expression is increased in ADT treated PCa patients regardless of TMPRSS2:ERG status. Corroborated in both in vivo LNCaP xenograft mouse and in vitro PCa cell line models which demonstrated a significant increase in CaV1.3 protein expression following ADT with bicalutamide. The expression was found to be a shortened 170kDA CaV1.3 isoform associated which failed to mediate calcium influx following membrane depolarisation. Instead, under ADT CaV1.3 mediated a rise in basal cytosolic calcium and an increase in store operated calcium entry (SOCE). This in turn drove both proliferation and survival of long-term ADT CRPC cells. Overall, this study demonstrates for the first time in PCa that increased SOCE through a novel CaV1.3 mechanism which represents a novel oncogenic switch that contributes to ADT resistance and promotes CRPC biology. Highlighting aberrant intracellular calcium in CRPC as a potential area for therapeutic development to improve patient outcomes. ### Competing Interest Statement The authors have declared no competing interest. * (ADT) : Androgen Deprivation Therapy (AR) : Androgen Receptor (Ca2+) : Calcium (CCB) : Calcium Channel Blocker (CRPC) : Castrate Resistant Prostate Cancer (CIM) : Cellular Invasion and Migration (CFA) : Colony Formation Assay (Cac2+) : Cytosolic Calcium (GAPDH) : Glyceraldehyde 3-phosphate dehydrogenase (IF) : Immunofluorescence (Cai2+) : Intracellular Calcium (MCT) : Multiple Comparison Test (PCa) : Prostate Cancer (Tg) : Thapsigargin (TMA) : Tumour Microarrays (SiCaV1.3) : siRNA CaV1.3 (sictr) : SiRNA Control (SOC) : Store Operated Current (SOCE) : Store Operated Calcium Entry (VGCC) : Voltage Gated Calcium Channels