The Two-Way Relationship Between Calcium and Metabolism in Cancer

Calcium ion (Ca²⁺) signaling is critical to many physiological processes, and its kinetics and subcellular localization are tightly regulated in all cell types. All Ca²⁺ flux perturbations impact cell function and may contribute to various diseases, including cancer. Several modulators of Ca²⁺ signaling are attractive pharmacological targets due to their accessibility at the plasma membrane. Despite this, the number of specific inhibitors is still limited, and to date there are no anticancer drugs in the clinic that target Ca²⁺ signaling. Ca²⁺ dynamics are impacted, in part, by modifications of cellular metabolic pathways. Conversely, it is well established that Ca²⁺ regulates cellular bioenergetics by allosterically activating key metabolic enzymes and metabolite shuttles or indirectly by modulating signaling cascades. A coordinated interplay between Ca²⁺ and metabolism is essential in maintaining cellular homeostasis. In this review, we provide a snapshot of the reciprocal interaction between Ca²⁺ and metabolism and discuss the potential consequences of this interplay in cancer cells. We highlight the contribution of Ca²⁺ to the metabolic reprogramming observed in cancer. We also describe how the metabolic adaptation of cancer cells influences this crosstalk to regulate protumorigenic signaling pathways. We suggest that the dual targeting of these processes might provide unprecedented opportunities for anticancer strategies. Interestingly, promising evidence for the synergistic effects of antimetabolites and Ca²⁺-modulating agents is emerging.