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The calcium–cancer signalling nexus

Nature Reviews Cancer volume 17, pages 373–380 (2017)Cite this article

Subjects

Key Points

  • Calcium is a ubiquitous but nuanced cellular signal; it regulates functions as diverse as cell motility, cell division and cell death. Precise control of the temporal and spatial aspects of calcium changes enable the signal to achieve specific cellular outcomes.

  • The nature of the calcium signal is controlled by a diverse array of calcium channels and pumps, and exchangers present on the plasma membrane and membranes of intracellular organelles. Certain cancers are associated with the remodelling of the expression of some of these proteins.

  • Calcium channels and pumps are amenable to targeting by pharmacological agents.

  • Calcium and calcium-regulating proteins contribute to many of the processes key to cancer cells, including proliferation, invasion and cell death. Several oncogenes and tumour suppressors have effects on calcium homeostasis.

  • Calcium signalling in the tumour microenvironment is likely to be a complex interplay between several different stromal cell types and cancer cells and represents new opportunities for therapeutic intervention.

  • The calcium signal is a crucial regulator of processes associated with tumour progression, including epithelial to mesenchymal transition and the acquisition of specific pathways important in therapeutic resistance.

  • The application of new methods to assess calcium signalling in vivo and over long periods of time will provide new insights into the remodelling of calcium signalling in cancer.

Abstract

The calcium signal is a powerful and multifaceted tool by which cells can achieve specific outcomes. Cellular machinery important in tumour progression is often driven or influenced by changes in calcium ions; in some cases this regulation occurs within spatially defined regions. Over the past decade there has been a deeper understanding of how calcium signalling is remodelled in some cancers and the consequences of calcium signalling on key events such as proliferation, invasion and sensitivity to cell death. Specific calcium signalling pathways have also now been identified as playing important roles in the establishment and maintenance of multidrug resistance and the tumour microenvironment.

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Figure 1: Examples of Ca2+-permeable channels and pumps, and exchangers of the plasma membrane and intracellular organelles.
Figure 2: Ca2+ signal diversity.
Figure 3: The Ca2+ signal and tumour progression.

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Acknowledgements

This work is supported by the National Health and Medical Research Council of Australia (1079671 and 1079672). G.M. is supported by the Mater Foundation. The Translational Research Institute is supported by a grant from the Australian government.

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Authors and Affiliations

  1. The School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Brisbane, 4102, Queensland, Australia

    Gregory R. Monteith & Sarah J. Roberts-Thomson

  2. Mater Research Institute, The University of Queensland, Brisbane, 4102, Queensland, Australia

    Gregory R. Monteith

  3. Translational Research Institute, Brisbane, 4102, Queensland, Australia

    Gregory R. Monteith

  4. Institut National de la Santé et de la Recherche Médicale U1003, Laboratoire de Physiologie Cellulaire, Equipe labellisée par la Ligue contre le cancer, and Universite de Lille 1, Villeneuve d'Ascq, F-59650, France

    Natalia Prevarskaya

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G.R.M. and S.J.R.T. are associated with QUE-Oncology, Inc. N.P. declares no competing interests.

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Glossary

Ca2+ channel

A protein or group of proteins that form a Ca2+-permeable pore across a membrane, which can be opened or closed by different stimuli.

Ca2+ pump

A protein that through the hydrolysis of ATP can transport Ca2+ against a concentration gradient; also referred to as Ca2+-ATPases.

Exchangers

Transporters of ions that involve the exchange of one type of ion for another type across a membrane, that does not involve the direct cleavage of ATP.

Store-operated calcium entry

(SOCE). A calcium ion (Ca2+) influx pathway activated upon the depletion of intracellular endoplasmic reticulum Ca2+ stores. The canonical pathway involves Ca2+ influx through calcium release-activated calcium channel protein 1 (ORAI1) after action by the endoplasmic reticulum Ca2+ sensor stromal interaction molecule 1 (STIM1).

Ca2+/calmodulin-dependent protein kinases

(CaMKs). Serine/threonine protein kinases, the activation of which is usually dependent on binding to calmodulin (CaM) in the calcium ion (Ca2+)-bound state.

Extracellular calcium-sensing receptor

(CaSR). A plasmalemmal G-protein-coupled receptor activated by changes in levels of extracellular free calcium ion.

Invadopodia

Plasma membrane protrusions associated with degradation of the extracellular matrix, which is important in cancer cell invasion.

Calcium ionophore

A chemical moiety that can facilitate increases in cytosolic free Ca2+ ([Ca2+]CYT) independently of Ca2+ channel activation.

Calcium electroporation

A process whereby an electrical field that increases the permeability of the plasma membrane of cells is applied in the presence of raised extracellular calcium ion concentration.

Necroptosis

A regulated form of necrotic cell death.

Autophagy

A physiological process involving degradation of the cells own components, which can be initiated by nutrient deficiency and can aid cell survival.

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Monteith, G., Prevarskaya, N. & Roberts-Thomson, S. The calcium–cancer signalling nexus. Nat Rev Cancer 17, 373–380 (2017). https://doi.org/10.1038/nrc.2017.18

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