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• W3197143912 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), for which there is an unmet therapeutic need. Altered calcium channel function and expression is known to lead to aberrant intracellular calcium (Cai2+) which promotes neoplastic transformation. There is growing evidence that expression of the voltage gated calcium channel (VGCC) family is increased in cancer, in particular the L-type channel 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 PCa patients with ongoing or post ADT compared to those with no treatment. 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. The expression of which was found to be a shortened 170kDA CaV1.3 isoform associated with intracellular membrane organelles. This isoform failed to mediate calcium influx through its canonical mechanism following membrane depolarisation. Instead, under ADT it mediated a rise in basal cytosolic calcium and an increase in store operated calcium entry (SOCE) through a non-canonical mechanism. This novel CaV1.3 mediated SOCE was linked to both proliferation and survival of long-term ADT CRPC cells. Overall, this study demonstrates for the first time in PCa that increased SOCE through CaV1.3 represents a novel oncogenic mechanism that contributes to ADT resistance and promotes CRPC biology. This highlights aberrant intracellular calcium in CRPC as a potential area for therapeutic development that could lead to improved patient outcomes." @default.
• W3197143912 created "2021-09-13" @default.
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• W3197143912 date "2021-09-04" @default.
• W3197143912 modified "2023-10-16" @default.
• W3197143912 title "CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer" @default.
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• W3197143912 doi "https://doi.org/10.1101/2021.09.03.458558" @default.
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