Anti-epidermal growth factor receptor monoclonal antibody 225 up-regulates p27KIP1 and induces G1 arrest in prostatic cancer cell line DU145.
Autocrine production of transforming growth factor alpha 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 p27KIP1. The increased p27KIP1 levels were attributable to elevation of both transcription and translation. CDK2 associated with p27KIP1 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 p27KIP1 at both the mRNA and protein levels.
Peng
D
D
Laboratory of Receptor Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Fan
Z
Z
Lu
Y
Y
DeBlasio
T
T
Scher
H
H
Mendelsohn
J
J
D000911:Antibodies, Monoclonal / Q000276:immunology*; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D002455:Cell Division; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D016193:G1 Phase; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D000911:Antibodies, Monoclonal; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases