CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer. (May 2022)

• Record Type: Journal Article
• Authors: O'Reilly, Debbie; Downing, Tim; Kouba, Sana; Potier-Cartereau, Marie; McKenna, Declan J.; Vandier, Christophe; Buchanan, Paul J.
• Is Part Of: Cell calcium. Volume 103(2022)
• Publication Date: 2022-05
• Subjects: Prostate Cancer -- Androgen Deprivation Therapy -- CaV1.3 -- Store operated calcium entry -- CACNA1D -- Aberrant Intracellular Calcium -- Abbreviations -- Androgen Deprivation Therapy (ADT) -- Androgen Receptor (AR) -- Calcium (Ca2+) -- Calcium Channel Blocker (CCB) -- Castrate Resistant Prostate Cancer (CRPC) -- Cellular Invasion and Migration (CIM) -- Colony Formation Assay (CFA) -- Cytosolic Calcium (Cac2+) -- Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) -- Immunofluorescence (IF) -- Intracellular Calcium (Cai2+) -- Log2 fold-change (LogFC) -- Multiple Comparison Test (MCT) -- Principal Components Analysis (PCA) -- Prostate Cancer (PCa) -- Quality Control (QC) -- Thapsigargin (Tg) -- Tumour Microarrays (TMA) -- siRNA CaV1.3 (SiCaV1.3) -- SiRNA Control (sictr) -- Short Tandem Array (STR) -- Store Operated Current (SOC) -- Store Operated Calcium Entry (SOCE) -- Voltage Gated Calcium Channels (VGCC); 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 -- LogFC Log2fold-change -- MCT Multiple Comparison Test -- PCA Principal Components Analysis -- PCa Prostate Cancer -- QC Quality Control -- Tg Thapsigargin -- TMA Tumour Microarray -- SiCaV1.3 siRNA CaV1.3 -- sictr SiRNA Control -- STR Short Tandem Array -- SOC Store Operated Current -- SOCE Store Operated Calcium Entry -- VGCC Voltage Gated Calcium Channels; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2022.102554
• Languages: English
• ISSNs: 0143-4160

Abstract

Highlights: CaV1.3 is upregulated in prostate cancer during androgen deprivation therapy Expression of short 170kDa isoform determines CaV1.3 function in PCa Store operated calcium entry is enhanced through CaV1.3 under androgen deprivation Androgen independent proliferation and survival is linked to CaV1.3 calcium entry CaV1.3 represents a novel oncochannel linked to castrate resistant prostate cancer Abstract: 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 (Cai 2+ ) is known to promote neoplastic transformation and treatment resistance. There is growing evidence that voltage gated calcium channel (VGCC) expression is increased in cancer, particularly 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 Cai 2+ and cancer biology. Bioinformatic analysis revealed that CACNA1D gene expression is increased in ADT treated PCa patients. This was 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. Expression was found to be of a shortened 170kDa CaV1.3 isoform associated with plasma and intracellular membranes, which failed to induce 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 mechanism was found to promote the proliferation and survival of ADT resistant CRPC cells. Overall, this study demonstrates for the first time in PCa that under ADT specific CaV1.3 isoforms promote an upregulation of SOCE which contributes to treatment resistance and CRPC biology. Thus, this novel oncochannel represents a target for therapeutic development to improve PCa patient outcomes. Graphical Abstract: Graphical Abstract Image, graphical abstract .