Regucalcin in the Tumor Microenvironment: From Intracellular Tumor Suppression to Putative Extracellular Signaling

Regucalcin (RGN), also known as senescence marker protein-30, is a calcium-binding protein without an EF-hand motif that regulates intracellular calcium homeostasis and Ca2+-dependent enzyme activity. Its expression is reduced in tumor tissue relative to matched normal tissue across several cancer types, and restoring RGN in cancer cell lines suppresses proliferation, migration, and invasion through cell cycle arrest, reduced expression of matrix metalloproteinases and epithelial–mesenchymal transition regulators, and transcriptional reprogramming involving p53, p21, Rb, c-myc, and β-catenin. Attention has more recently turned to RGN outside the cell. RGN is detectable in serum and interstitial fluid, and recombinant RGN applied to cancer cells reproduces much of the suppression seen upon intracellular overexpression, which has prompted the proposal that extracellular RGN acts within the tumor microenvironment (TME). That proposal, however, rests on evidence that remains incomplete. RGN carries no classical signal peptide and its route of release is undefined; it has been reported in extracellular vesicle preparations but has not been shown to be a bona fide vesicular cargo; no receptor or proximal binding partner has been identified; and its effects on the non-malignant compartment of the TME—fibroblasts, immune cells, and endothelium—have not been tested directly. Here, we review the tumor-suppressive activity of RGN, distinguish demonstrated findings from inferred ones, and outline the experiments required to determine whether extracellular RGN constitutes a signaling axis in the TME or a pharmacological property of a recombinant protein.