The effect of trifluoperazine, a calmodulin antagonist, on the growth of normal and malignant epidermal keratinocytes in culture.

Calmodulin, a cytoplasmic calcium binding protein, is present in concentrations two- to four-fold higher in malignant cells compared to normal cells. In an effort to learn the significance of these elevated levels, we examined the effect of calmodulin blockage on the growth of normal and malignant keratinocytes in vitro. The level of calmodulin in SCC12.B2, a line of keratinocytes derived from an epidermal squamous cell carcinoma (SCC), was about 3.5 times greater than in normal, human newborn foreskin keratinocytes. When exposed to trifluoperazine (TFP), an inhibitor of calmodulin, cell growth was reduced primarily in the cultures of normal keratinocytes. This growth inhibition resulted from two changes in the replicating population of cells, namely an increase in cell cycle length and an increase in rate of cell cycle withdrawal. Cell cycle withdrawal is the irreversible arrest of the cell cycle and is an early event in keratinocyte terminal differentiation. There was no measurable effect on the cell cycle time or withdrawal rate in SCC12.B2. The increased resistance to growth arrest in SCC cells may be a consequence of the elevated level of calmodulin in these cells.