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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?