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Identification of Channels Promoting Calcium Spikes and Waves in HT1080 Tumor Cells

Their Apparent Roles in Cell Motility and Invasion

Departments of ¹ Ophthalmology and Visual Sciences and ² Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor, Michigan

Intracellular Ca²⁺ signals have been associated with cell polarization and locomotion. As cell motility underlies metastasis, we have sought to better characterize the Ca²⁺ signaling events in HT1080 fibrosarcoma cells. We have tested the hypothesis that low voltage-activated (LVA) and nonvoltage-gated (NVG) channels of HT1080 cells participate in dynamic Ca²⁺-signaling events leading to cell migration and invasion. Immunofluorescence microscopy has shown that HT1080 cells express LVA T-type Ca²⁺ channels uniformly about the cell periphery, whereas the transient receptor potential-1 (a NVG cation channel) protein appears as punctate spots about a cell’s periphery. HT1080 cells exhibit periodic intracellular Ca²⁺ spikes. High-speed imaging revealed that the Ca²⁺ spikes were composed of a single Ca²⁺ wave traveling unidirectionally about the periphery of the cytoplasm in a clockwise fashion (as viewed from basal to apical surfaces). The T-type Ca²⁺ channel blocker mibefradil inhibited Ca²⁺ spikes and waves on cells and, in parallel, inhibited cell motility and invasion in a dose-dependent manner. Similar changes were noted with the NVG cation channel blockers Gd³⁺ and carboxyamido-triazole. The combination of LVA and NVG blockers further reduced Matrigel invasiveness. However, the Ca²⁺ channel blockers nicardipine, SKF96365, diltiazem, and verapamil had no effect at appropriate doses. These results indicate that certain LVA and NVG channels regulate HT1080 cell motility. In addition to providing novel information regarding cancer cell motility, we suggest that it may be possible to design drugs that inhibit a key Ca²⁺ wave, thereby enhancing the efficacy of emerging therapeutic protocols.

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