title: Cancer dormancy: role of cyclin-dependent kinase inhibitors in induction of cell cycle arrest mediated via membrane IgM.
abstract: Anti-idiotype (anti-Id) antibody can induce tumor dormancy in a murine B lymphoma, BCL1, by its ability to induce cell cycle arrest and apoptosis (negative signaling). In human B lymphoma, there is accumulating evidence that the antitumor effect of anti-Id or several other B cell-reactive antibodies relates to their ability to act as agonists rather than conventional effector antibodies. In this study, we sought to elucidate the role of cyclins, cyclin-dependent kinases (CDKs), and their inhibitors in anti-IgM-induced cell cycle arrest to better understand the mechanisms underlying cancer dormancy. To accomplish this, we have performed in vitro studies with a human lymphoma cell line (Daudi) because its response to anti-Id (or anti-IgM) is similar to that of a BCL1 cell line, more reagents are available, and the results would be particularly pertinent to therapy of human B cell lymphomas. Our results show that cross-linking of membrane IgM on Daudi cells induces an arrest late in G1 and prevents pRb from becoming phosphorylated. The G1 arrest is correlated with an induction of the CDK inhibitor p21 and reduced CDK2 activity, although the level of CDK2 protein was not changed. Coprecipitation of CDK2 with p21 in anti-IgM-treated cells and the unchanged level of cyclin E suggest that p21 is responsible for the reduction of CDK2 activity and therefore blockade of the cell cycle. The induction of p21 was not accompanied by changes in p53 levels. As a result of the G1 block, cyclin A levels sharply declined by 24 h after anti-IgM treatment. There was no evidence for involvement of CDK4 or CDK6 in the blockade. These results provide evidence that membrane IgM cross-linking on Daudi cells induces expression of p21 and a subsequent inhibition of the cyclin E-CDK2 kinase complex resulting in a block to pRb phosphorylation and cell cycle arrest late in G1.
authors.affiliation: Cancer Immunobiology Center and Department of Microbiology, University of Texas Southwestern Medical Center at Dallas, 75235-8576, USA.
authors.forename: R
authors.initials: R
authors.lastname: Marches
authors.forename: R H
authors.initials: RH
authors.lastname: Scheuermann
authors.forename: J W
authors.initials: JW
authors.lastname: Uhr
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D002051:Burkitt Lymphoma; D002453:Cell Cycle; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000502:physiology*; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D016192:Resting Phase, Cell Cycle; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000888:Antibodies, Anti-Idiotypic; D016213:Cyclins; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D016160:Retinoblastoma Protein; D018844:Cyclin-Dependent Kinases