ANTIEPIDERMAL GROWTH-FACTOR RECEPTOR MONOCLONAL-ANTIBODY-225 UP-REGULATES P27(KIP1) AND INDUCES G(1) ARREST IN PROSTATIC-CANCER CELL-LINE DU145

Autocrine production of transforming growth factor ru and overexpressi on of the epidermal growth factor receptor (EGFR) may contribute to an drogen-independent prostatic cancer growth at both primary and metasta tic sites. Previously, we showed that human EGFR-blocking monoclonal a ntibody mAb225 inhibited the growth of DU145 human prostatic cancer ce lls, Here we explore the hypothesis that mAb225 may act by interfering with cell cycle traversal in these cells. Treatment with mAb225 induc ed G(1) arrest, which was accompanied by a marked decrease In CDK2-, c yclin A-, and cyclin E-associated histone H1 kinase activities, and a sustained increase in cell cycle inhibitor p27(KIP1). Th, increased p2 7(KIP1) levels were attributable to elevation of both transcription an d translation. CDK2 associated with p27(KIP1) was increased in mAb225- treated DU145 cells. The retinoblastoma-related protein p130 remained hypophosphorylated in these retinoblastoma-negative cells. These studi es demonstrate that the antiproliferative effect of EGFR blockade in D U145 cells may be mediated by up-regulation of p27(KIP1) at both the m RNA and protein levels.