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  • Review Article
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Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival

Key Points

  • Changes in Ca2+ levels are versatile and dynamic signalling events that control diverse cellular events over a wide range of timescales.

  • Tumour cells are characterized by their acquisition of different physiological traits that allow them to proliferate independently of growth signals and avoid appropriate cell death.

  • The Ca2+ signalling 'toolkit' — that is, the proteins involved in regulating Ca2+ signalling — is often remodelled in tumour cells to sustain proliferation and avoid cell death.

  • Ca2+ signalling proteins and organelles are emerging as additional cellular targets of oncogenes and tumour suppressors.

  • Ca2+ signalling pathways remodelled in cancer provide novel opportunities for therapeutic intervention.

Abstract

Increases in cytosolic free Ca2+ ([Ca2+]i) represent a ubiquitous signalling mechanism that controls a variety of cellular processes, including proliferation, metabolism and gene transcription, yet under certain conditions increases in intracellular Ca2+ are cytotoxic. Thus, in using Ca2+ as a messenger, cells walk a tightrope in which [Ca2+]i is strictly maintained within defined boundaries. To adhere to these boundaries and to sustain their modified phenotype, many cancer cells remodel the expression or activity of their Ca2+ signalling apparatus. Here, we review the role of Ca2+ in promoting cell proliferation and cell death, how these processes are remodelled in cancer and the opportunities this might provide for therapeutic intervention.

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Figure 1: The Ca2+ signalsome.
Figure 2: Ca2+ and the cell cycle.
Figure 3: Ca2+-dependent signalling pathways controlling the G1/S transition.
Figure 4: Ca2+-dependent activation and inactivation of Ras.
Figure 5: Apoptotic signals that induce endoplasmic reticulum (ER)–mitochondrial Ca2+ flux and their remodelling during cancer.

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Acknowledgements

The authors would like to acknowledge M. Bootman (Babraham Institute) for insightful discussions and critical reading of the manuscript. Work in the authors' research groups is funded by the Babraham Institute, Association for International Cancer Research, AstraZeneca, the Biotechnology and Biological Sciences Research Council, the British Heart Foundation and the Royal Society.

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National Cancer Institute

breast cancer

colorectal cancer

gastric cancer

glioblastoma

glioma

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lung cancer

nasopharyngeal cancer

neuroblastoma

oesophageal cancer

osteosarcoma

prostate cancer

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National Cancer Institute Drug Dictionary

ceramide

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Glossary

Driver mutation

A mutation that contributes intimately to tumorigenesis and is selected for during tumour evolution, as opposed to a passenger mutation, which confers no selective advantage and is 'along for the ride'.

T-type Ca2+ channel

Voltage-operated Ca2+ channel that is activated at relatively negative membrane potential and exhibits a short-lasting (transient) opening.

S100 proteins

A family of EF-hand-containing Ca2+ binding proteins.

CpG island

A DNA region of >500 base pairs that has a high CpG density and is usually unmethylated. CpG islands are found upstream of many mammalian genes; methylation leads to transcriptional silencing.

AP1

A transcription factor that is composed of JUN, FOS, MAF and ATF proteins in various combinations.

Caspases

A family of cysteine-dependent proteases, evolutionarily conserved from Caenorhabditis elegans, which are involved in the initiation and execution of cell death pathways.

BAX/BAK knockout cells

Cells that do not express the pro-apoptotic proteins BAX and BAK are resistant to many cell death stimuli.

Reactive oxygen species

Highly unstable oxygen-containing chemical entities (such as O2- and H2O2) that have both a role in pathology and cell signalling.

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Roderick, H., Cook, S. Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival. Nat Rev Cancer 8, 361–375 (2008). https://doi.org/10.1038/nrc2374

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