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Suppression of EGF‐induced cell proliferation by the blockade of Ca2+ mobilization and capacitative Ca2+ entry in mouse mammary epithelial cells

The role of intracellular Ca2+ stores and capacitative Ca2+ entry on EGF‐induced cell proliferation was investigated in mouse mammary epithelial cells. We have previously demonstrated that EGF enhances Ca2+ mobilization (release of Ca2+ from intracellular Ca2+ stores) and capacitative Ca2+ entry correlated with cell proliferation in mouse mammary epithelial cells. To confirm their role on EGF‐induced cell cycle progression, we studied the effects of 2,5‐di‐tert‐butylhydroquinone (DBHQ), a reversible inhibitor of the Ca2+ pump of intracellular Ca2+ stores, and SK&38;F 96365, a blocker of capacitative Ca2+ entry, on mitotic activity induced by EGF. Mitotic activity was examined using an antibody to PCNA for immunocytochemistry. SK&38;F 96365 inhibited capacitative Ca2+ entry in a dose‐dependent manner (I50: 1–5μm). SK&38;F 96365 also inhibited EGF‐induced cell proliferation in the same range of concentration (I50: 1–5 μm). DBHQ suppressed [Ca2+]i response to UTP and thus depleted completely Ca2+ stores at 5 μm. DBHQ also inhibited EGF‐induced cell proliferation at an I50 value of ∼10 μm. The removal of these inhibitors from the culture medium increased the reduced mitotic activity reversibly. Using a fluorescent assay of DNA binding of ethidium bromide, no dead cells were detected in any of the cultures. These results indicate that the inhibitory effects of SK&38;F 96365 and DBHQ on cell proliferation were due to the inhibition of capacitative Ca2+ entry and Ca2+ mobilization suggesting the importance of capacitative Ca2+ entry and Ca2+ mobilization in the control of EGF‐induced cell cycle progression in mouse mammary epithelial cells. Copyright © 2001 John Wiley & Sons, Ltd.