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Anti-Epidermal Growth Factor Receptor Monoclonal Antibody 225 Up-Regulates p27^KIP1 and Induces G₁ Arrest in Prostatic Cancer Cell Line DU145¹

Laboratory of Receptor Biology, Program in Molecular Pharmacology and Therapeutics [D. P., Z. F., Y. L., T. D., J. M.], Genitourinary Oncology Service [H. S.], and Department of Medicine [Z. F., H. S., J. M.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021; and Department of Medicine, Cornell University Medical College, New York, NY 10021 [H. S., J. M.]

Autocrine production of transforming growth factor and overexpression of the epidermal growth factor receptor (EGFR) may contribute to androgen-independent prostatic cancer growth at both primary and metastatic sites. Previously, we showed that human EGFR-blocking monoclonal antibody mAb225 inhibited the growth of DU145 human prostatic cancer cells. Here we explore the hypothesis that mAb225 may act by interfering with cell cycle traversal in these cells. Treatment with mAb225 induced G₁ arrest, which was accompanied by a marked decrease in CDK2-, cyclin A-, and cyclin E-associated histone H1 kinase activities, and a sustained increase in cell cycle inhibitor p27^KIP1. The increased p27^KIP1 levels were attributable to elevation of both transcription and 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 studies demonstrate that the antiproliferative effect of EGFR blockade in DU145 cells may be mediated by up-regulation of p27^KIP1 at both the mRNA and protein levels.

¹ This study was supported in part by grants from CaPCURE and the Pepsi Co. Foundation. J. M. was supported by NIH Grants CA42060 and CA37641. H. S. was supported by NIH Grant CA05826.

² The first two authors contributed equally to this study.

³ To whom requests for reprints should be addressed, at the University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 91, Houston, TX 77030.

Received 5/23/96. Accepted 7/15/96.

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