The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

Abstract

Calmodulin (CaM) is the principal Ca2+ sensor protein in all eukaryotic cells, that upon binding to target proteins transduces signals encoded by global or subcellular-specific changes of Ca2+ concentration within the cell. The Ca2+/CaM complex as well as Ca2+-free CaM modulate the activity of a vast number of enzymes, channels, signaling, adaptor and structural proteins, and hence the functionality of implicated signaling pathways, which control multiple cellular functions. A basic and important cellular function controlled by CaM in various ways is cell motility. Here we discuss the role of CaM-dependent systems involved in cell migration, tumor cell invasiveness, and metastasis development. Emphasis is given to phosphorylation/dephosphorylation events catalyzed by myosin light-chain kinase, CaM-dependent kinase-II, as well as other CaM-dependent kinases, and the CaM-dependent phosphatase calcineurin. In addition, the role of the CaM-regulated small GTPases Rac1 and Cdc42 (cell division cycle protein 42) as well as CaM-binding adaptor/scaffold proteins such as Grb7 (growth factor receptor bound protein 7), IQGAP (IQ motif containing GTPase activating protein) and AKAP12 (A kinase anchoring protein 12) will be reviewed. CaM-regulated mechanisms in cancer cells responsible for their greater migratory capacity compared to non-malignant cells, invasion of adjacent normal tissues and their systemic dissemination will be discussed, including closely linked processes such as the epithelial–mesenchymal transition and the activation of metalloproteases. This review covers as well the role of CaM in establishing metastatic foci in distant organs. Finally, the use of CaM antagonists and other blocking techniques to downregulate CaM-dependent systems aimed at preventing cancer cell invasiveness and metastasis development will be outlined.

Phosphoinositide-Dependent Signaling in Cancer: A Focus on Phospholipase C Isozymes

“…More importantly, the promotion of cell migration by Tpl2 was dependent on both pathways. PLC-mediated Ca 2+ influx has been demonstrated to promote the disassembly of focal adhesions at the rear of migrating cells and assembly of focal adhesions at the leading edge, an essential event in migrating cells [27,108]. In support of this study, there is mounting evidence of the ability of the downstream effectors of PLCγ, PKC and Ca 2+ to support cell migration, by regulating cell adhesion turnover and acto-myosin contractility [46].…”

Expression of CAMK1 and its association with clinicopathologic characteristics in pancreatic cancer

“…In human body, CaM transmits information to many interaction partners by sensing local changes in Ca2 + concentration. Ca2+/CaM complex can modulate the activities of enzymes, channels, signals, adaptor and structural proteins, thereby regulating the functions of related signalling pathways that control various cell functions 21‐23 . It is reported that CaM can regulate cell growth and its function may change in malignant tumours 24,25 .…”

Deciphering the Role of Ca2+ Signalling in Cancer Metastasis: From the Bench to the Bedside

“…Calmodulin (CaM) is a multifunctional Ca 2+ binding protein. Its role in metastatic traits was recently reviewed by Villalobo, and Martin, providing valuable insight into the roles of calmodulin in metastasis, from invasiveness to tumour cell migration [ 136 ]. It was shown that calcium/calmodulin-dependent protein kinase II (CaMKII) triggered gastric cancer cell metastasis by activating nuclear factor-κB (NF-κB) signalling involving AKT, which ultimately enhanced MMP-9production in BGC-803 cells (an in vitro model of human gastric cancer) [ 137 ]; this is a metastatic prompting protein present in various cancer subtypes.…”