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Calcium signalling pathways in prostate cancer initiation and progression

Nature Reviews Urology volume 20, pages 524–543 (2023)Cite this article

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Abstract

Cancer cells proliferate, differentiate and migrate by repurposing physiological signalling mechanisms. In particular, altered calcium signalling is emerging as one of the most widespread adaptations in cancer cells. Remodelling of calcium signalling promotes the development of several malignancies, including prostate cancer. Gene expression data from in vitro, in vivo and bioinformatics studies using patient samples and xenografts have shown considerable changes in the expression of various components of the calcium signalling toolkit during the development of prostate cancer. Moreover, preclinical and clinical evidence suggests that altered calcium signalling is a crucial component of the molecular re-programming that drives prostate cancer progression. Evidence points to calcium signalling re-modelling, commonly involving crosstalk between calcium and other cellular signalling pathways, underpinning the onset and temporal progression of this disease. Discrete alterations in calcium signalling have been implicated in hormone-sensitive, castration-resistant and aggressive variant forms of prostate cancer. Hence, modulation of calcium signals and downstream effector molecules is a plausible therapeutic strategy for both early and late stages of prostate cancer. Based on this premise, clinical trials have been undertaken to establish the feasibility of targeting calcium signalling specifically for prostate cancer.

Key points

  • Calcium is a ubiquitous ion that has crucial roles in many cellular pathways.

  • Aberrations in calcium signalling can result in pathogenic phenotypes, including cancer.

  • The onset and progression of prostate cancer are characterized by the altered expression of several calcium signalling mediators, including TRPs, VGCCs, and ORAI–STIM.

  • Dysregulation of calcium signalling enhances the survival, proliferation, migration, invasiveness and drug resistance of prostate cancer cells, with discrete alterations in calcium signalling and downstream signalling outcomes occurring at different stages of cancer progression.

  • Targeting calcium signalling mediators is a promising strategy for developing novel drugs for treating prostate cancer and other malignancies.

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Fig. 1: Evolution of prostate cancer.
Fig. 2: Components of the calcium signalling toolkit.
Fig. 3: Dysregulation of calcium signalling toolkit components in prostate cancer.
Fig. 4: Calcium signalling toolkit components involved in bone metastases.
Fig. 5: Unified model of calcium signalling alterations in prostate cancer.

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  1. These authors contributed equally: Roberto Silvestri, Vanessa Nicolì.

Authors and Affiliations

  1. Department of Biology, University of Pisa, Pisa, Italy

    Roberto Silvestri

  2. Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy

    Vanessa Nicolì

  3. Cancer Research Group, School of Life Health and Chemical Sciences, The Open University, Milton Keynes, UK

    Priyadarsini Gangadharannambiar, Francesco Crea & Martin D. Bootman

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R.S., V.N. and P.G. researched data for the article. R.S., V.N., F.C. and M.D.B. contributed substantially to discussion of the content. All authors wrote the article. F.C. and M.D.B. reviewed and/or edited the manuscript before submission.

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Silvestri, R., Nicolì, V., Gangadharannambiar, P. et al. Calcium signalling pathways in prostate cancer initiation and progression. Nat Rev Urol 20, 524–543 (2023). https://doi.org/10.1038/s41585-023-00738-x

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