Calumenin, A Calcium-Binding Modulatory Protein, Effective in Pathological Calcifications and Cancers, With Therapeutic Application Promise.

Calumenin (CALU), a multifunctional E-F-hand protein of the CREC family involved in various cellular processes, is ubiquitously expressed in almost all human tissues, although its expression level is tissue-specific. CALU plays an effective role in calcium (Ca) homeostasis throughout various Ca2+-related processes, and its correlations with various ER-related functions are evident. Due to its propensity to bind Ca, participation in calcium ion (Ca2+)-dependent activities, major cellular processes, such as the production and maintenance of extracellular matrix, have been attributed to this multifaceted protein. In this regard, CALU's association with various normal calcification processes, as well as pathologic Ca deposits, is apparent. Additionally, its key role as a crossroads among various normal cellular processes and many inflammatory diseases and cancers is also evident. The important correlation of CALU with cancer-related proteins through its regulatory role in γ-carboxylation of known cancer-related vitamin K-dependent proteins has also been noted. The opposing and pleiotropic functions of the CALU isoforms might play balancing roles in establishing a state of equilibrium in the cell. Given the contradictory functions of CALU isoforms during cancer, the need for a balance between these isoforms, as well as the existence of mechanisms to regulate their ratio in normal cells, is speculated. The relationship between CALU and immune response, tumor-infiltrating immune cells, and cancer patients' responsiveness to various cancer therapies is also described. In this regard, the involvement of the CALU isoform in response to cancer treatment and various immune pathways is discussed. This comprehensive review addresses the outstanding features and the latest findings on CALU's molecular aspects and diverse functions in various physiological processes and pathological conditions.