Regulation of T-Type Ca2+ Channels in Cancer Cell Cycle

Abstract

Calcium signaling plays an important role in the regulation of cell cycling. Cells passing from G1 to S require both extracellular calcium and functional plasma membrane calcium channels in order to activate various downstream enzymes, such as ribonucleotide reductase, thymidine kinase, thymidylate synthase, and DNA polymerase. Fast proliferating cancer cells contain higher levels of basal [Ca2+]i than normal epithelial cells. Indeed, in order to compensate for the increased requirement for Ca2+ during periods of high rates of cell proliferation, cancer cells frequently express more T-type Ca2+ channels to provide an extra source for Ca2+ influx. Thus, blockade of T-type Ca2+ channels in cancer cells can synchronize the pace of cell cycling. Using such an “interlaced” therapeutic approach could enhance the effectiveness of chemotherapy. For example, if T-type Ca2+ channel blockers stopped proliferating cells near the G1/S checkpoint of the cell cycle, then at the cessation of calcium channel blocker treatment a relatively large population of tumor cells would enter S phase and be susceptible to S phase-specific chemotherapy.