Calcium-mediated signal transduction: biology, biochemistry, and therapy

The process of proliferation, invasion and metastasis is a complex one which involves both the autonomy of the malignant cells and their interaction with the cellular and extracellular environments. The way in which the tumor cells respond to cellular and extracellular stimuli is regulated through transduction of those signals and translation into cellular activity. Transmembrane signal transduction involves three major categories of events: ion channel activation, transmission through guanine nucleotide binding protein intermediates with production of second messengers, and phosphorylation events. A frequent common denominator of these different pathways is a cellular calcium homeostasis. Calcium may be both a result of and a regulator of many of these signal transduction pathways and has been shown to have a role in the regulation of proliferation, invasion, and metastatic potential. The understanding and application of the basic tenets of these pathways to tumor cell proliferation, invasion, and metastases opens a new target for therapeutic intervention. We have identified a novel agent, CAI, which through inhibition of stimulated calcium influx inhibits proliferation and migration in vitro, and growth and dissemination in human cancer xenografts in vivo. CAI offers a new approach to cancer therapy, signal transduction therapy.