Background: Colorectal cancer (CRC) is one of the most common malignancies and a leading cause of cancer-related mortality worldwide. Dysregulation of calcium homeostasis and calcium-dependent signaling pathways, particularly those mediated by calmodulin (CaM), plays a critical role in CRC initiation, progression, and metastasis. CaM acts as a central intracellular calcium ion (Ca²⁺) sensor that integrates calcium signals with multiple oncogenic pathways.
Materials and Methods: This narrative review summarizes current evidence on the role of CaM in CRC. Relevant studies published between 2000 and 2025 were identified through systematic searches of PubMed, Scopus, and Web of Science using keywords related to CaM, calcium signaling, Ca²⁺/CaM-dependent kinases, and CRC. Data from mechanistic, preclinical, and translational studies were qualitatively synthesized.
Results: The reviewed studies demonstrate that CaM promotes CRC cell proliferation through activation of Ca²⁺/CaM-dependent kinases, particularly CaM-dependent protein kinases (CaM-KII), leading to stimulation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), and Wnt/β-catenin signaling pathways. CaM also enhances tumor progression and metastasis by regulating cytoskeletal dynamics, epithelial–mesenchymal transition, matrix metalloproteinase activity, and interactions with oncogenic partners, such as epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS). Pharmacological inhibition of CaM in preclinical CRC models reduces cell growth, invasion, and resistance to chemotherapy.
Conclusion: CaM is a key signaling hub in CRC, linking calcium dynamics to proliferation, survival, and metastatic behavior. Selective targeting of CaM-dependent signaling or CaM–oncoprotein interactions represents a promising therapeutic strategy for precision management of CRC.