The
geranylgeranyltransferase I inhibitor
GGTI-298 has recently been shown to arrest human
tumor cells in the G1 phase of the cell cycle, induce apoptosis, and inhibit
tumor growth in nude mice. In the present manuscript, we provide a possible mechanism by which
GGTI-298 mediates its
tumor growth arrest. Treatment of the human lung
carcinoma cell line Calu-1 with
GGTI-298 results in inhibition of the phosphorylation of
retinoblastoma protein, a critical step for G1/S transition. The
kinase activities of two G1/S
cyclin-dependent kinases, CDK2 and CDK4, are inhibited in Calu-1 cells treated with
GGTI-298. Furthermore,
GGTI-298 has little effect on the expression levels of CDK2, CDK4, CDK6,
cyclins D1 and E, but decreases the levels of
cyclin A.
GGTI-298 increases the levels of the
cyclin-dependent kinase inhibitors p21 and p15 and had little effect on those of p27 and p16. Most interesting is the ability of
GGTI-298 to induce partner switching for several CDK inhibitors.
GGTI-298 promotes binding of p21 and p27 to CDK2 while decreasing their binding to CDK6. Reversal of partner switching and G1 block was observed after removal of
GGTI-298. Furthermore,
GGTI-298 treatment results in an increased binding of p15 to CDK4, which is paralleled with decreased binding to p27. The results demonstrate that the GGTI-298-mediated G1 block in Calu-1 cells involves increased expression and partner switching of CDK inhibitors resulting in inhibition of CDK2 and CDK4, and
retinoblastoma protein phosphorylation.