Inhibition of cdk2 kinase activity by methylselenocysteine in synchronized mouse mammary epithelial tumor cells

Methylselenocysteine (MSC), an organic selenium compound has significantanticarcinogenic activity against mammary tumorigenesis. Previousexperiments have demonstrated that MSC and inorganic selenite inhibitmammary cell (TM6 cell line) growth through different pathways. The presentinvestigation demonstrated that MSC arrested cells in S phase during theTM6 cell cycle, which was followed by cells entering apoptosis at 48 h.Methylselenocysteine specifically affected the cdk2 kinase activity of theTM6 cells (54% reduction) at 16 h after release from growth arrest. Thecdk4 kinase activity did not change during the cell cycle, confirming thatcells had passed the G1 checkpoint and had entered S phase. The amount ofcyclin E associated with cdk2 was increased by MSC by the 12 h time point,thereby facilitating entry of cells into S phase. Afterwards, cyclin E andcyclin A associated with cdk2 did not change for the remainder of the cellcycle. The data demonstrate that inhibition of mammary cell growth by MSCis mediated by alterations in progression of cells through S phase. Thedecrease in cdk2 kinase activity is coincident with prolonged arrest in Sphase. One consequence of prolonged arrest may be apoptosis.