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  • Review Article
  • Published:

Calcium and cancer: targeting Ca2+ transport

Nature Reviews Cancer volume 7, pages 519–530 (2007)Cite this article

Key Points

  • Ca2+ homeostasis controls various cellular processes, including those relevant to tumorigenesis, such as proliferation, apoptosis, gene transcription and angiogenesis.

  • Ca2+ channels, pumps and exchangers control the complex and tight regulation of Ca2+ homeostasis. Specific isoforms of these proteins are responsible for increasing or reducing cytosolic free Ca2+. These channels, pumps and exchangers differ in their cellular distribution and their mechanism of transport.

  • Some cancers are associated with the up- or downregulation of specific Ca2+ channels or pumps. For example, TRPM8 is upregulated in prostate cancer and SERCA3 is downregulated in colon cancer.

  • Many Ca2+ channels, pumps and exchangers are modulated by pharmacological agents and are regarded as druggable. The role of Ca2+ in both proliferation and apoptosis means that both inhibitors and activators of these proteins are potential therapeutic agents in cancer chemotherapy.

  • Questions remain as to which approach, and what channels and pumps, are likely to lead to the most effective cancer therapeutics.

Abstract

Ca2+ is a ubiquitous cellular signal. Altered expression of specific Ca2+ channels and pumps are characterizing features of some cancers. The ability of Ca2+ to regulate both cell death and proliferation, combined with the potential for pharmacological modulation, offers the opportunity for a set of new drug targets in cancer. However, the ubiquity of the Ca2+ signal is often mistakenly presumed to thwart the specific therapeutic targeting of proteins that transport Ca2+. This Review presents evidence to the contrary and addresses the question: which Ca2+ channels and pumps should be targeted?

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Figure 1: Ca2+ channels, pumps and exchangers and important regulatory domains.
Figure 2: Specificity of targeting an aberrantly expressed Ca2+ pump.
Figure 3: Duality of the Ca2+ signal and cancer cell death.

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Authors and Affiliations

  1. School of Pharmacy, The University of Queensland, Brisbane, Australia, 4072, Queensland

    Gregory R. Monteith, Damara McAndrew, Helen M. Faddy & Sarah J. Roberts-Thomson

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Sarah Roberts-Thomson and Gregory Monteith are recipients of a pathfinder grant awarded by UniQuest pty Ltd, a subsidiary company of the University of Queensland, Australia.

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Glossary

Ca2+ stores

Intracellular organelles (such as the endoplasmic reticulum; ER) that sequester and store Ca2+. Organelles such as the ER can release this stored Ca2+ through intracellular signals such as IP3 or through a Ca2+-induced Ca2+ release mechanism.

Ca2+ channel

A protein or protein complex capable of forming Ca2+-permeable pores in membranes. When channels are open, Ca2+ is able to diffuse through the pore, down its concentration gradient.

Ca2+ pump (ATPase)

A membrane Ca2+ transporter that uses energy derived from ATP hydrolysis to transport Ca2+ across membranes against their concentration gradient.

Exchanger

A secondary active transporter that derives energy from the flow of one ion down its concentration gradient, produced by primary active transport, to transport another ion against its concentration gradient.

Facilitated diffusion

The diffusion of molecules across membranes (either intracellular or the plasma membrane) assisted by proteins (such as Ca2+ channels).

Active transport

The transport of molecules across a biological membrane against their electrical or concentration gradient. This kind of transport requires an energy source. Primary active transporters (such as Ca2+ pumps) use energy derived from ATP. Secondary active transporters (such as Na+/Ca2+ exchangers) derive energy from the flow of one ion down its concentration gradient to transport another ion against its concentration gradient.

Ca2+ oscillations

Ca2+ signals that are periodic increases in [Ca2+]CYT. The concentration of a stimulus can often control the frequency of oscillations.

Chemogenomics

A drug discovery approach whereby information about a gene or protein family guides the drug development process. For example, a known pharmacological modulator of one member of a gene family could be used to guide the development of new pharmacological modulators for another family member, and provide information about potential structure–activity relationships.

Ca2+ waves

Increases in [Ca2+]CYT characterized as an initial increase in free Ca2+ in one area of the cell. These signals then propagate throughout the cell as an intracellular Ca2+ wave. In some cases the wave can spread throughout a cell population, termed an intercellular Ca2+ wave.

Sensory neuropathy

Can result from physical or chemical stimulus on the peripheral sensory neurons (known as nociceptors) owing to tissue injury caused directly by a tumour, or as a toxic side effect of therapies used to treat cancer. This can manifest as numbness or tremor, hyperalgesia (mild noxious sensory stimuli being perceived as highly noxious stimuli) or allodynia (normally non-noxious sensory stimuli being perceived as noxious stimuli).

Hyponatraemia

Deficiency of Na+ in the blood.

Ca2+ transient

A short increase in [Ca2+]CYT, usually caused by the opening of Ca2+ channels in the plasma membrane or on Ca2+ storage organelles.

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Monteith, G., McAndrew, D., Faddy, H. et al. Calcium and cancer: targeting Ca2+ transport. Nat Rev Cancer 7, 519–530 (2007). https://doi.org/10.1038/nrc2171

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