Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy

Intracellular Ca²⁺ distribution is a tightly regulated process. Numerous Ca²⁺ chelating, storage, and transport mechanisms are required to maintain normal cellular physiology. Ca²⁺-binding proteins, mainly calmodulin and calbindins, sequester free intracellular Ca²⁺ ions and apportion or transport them to signaling hubs needing the cations. Ca²⁺ channels, ATP-driven pumps, and exchangers assist the binding proteins in transferring the ions to and from appropriate cellular compartments. Some, such as the endoplasmic reticulum, mitochondria, and lysosomes, act as Ca²⁺ repositories. Cellular Ca²⁺ homeostasis is inefficient without the active contribution of these organelles. Moreover, certain key cellular processes also rely on inter-organellar Ca²⁺ signaling. This review attempts to encapsulate the structure, function, and regulation of major intracellular Ca²⁺ buffers, sensors, channels, and signaling molecules before highlighting how cancer cells manipulate them to survive and thrive. The spotlight is then shifted to the slow pace of translating such research findings into anticancer therapeutics. We use the PubMed database to highlight current clinical studies that target intracellular Ca²⁺ signaling. Drug repurposing and improving the delivery of small molecule therapeutics are further discussed as promising strategies for speeding therapeutic development in this area.