Cell Adhesion Induces p27Kip1-Associated Cell-Cycle Arrest through Down-Regulating SCF^Skp2 Ubiquitin Ligase Pathway in Mantle Cell and Other Non-Hodgkin’s B-Cell Lymphomas.

Mounting evidence now suggests that dynamic interactions between the tumor cell and its local and systemic microenvironment play a critical role in tumor development and that all of the clinical properties of a tumor, including cell cycle progression and response to therapy, depend heavily on the tumor stroma. However, the molecular mechanisms of the interaction between stroma and tumor cells are not well defined. In this study we used mantle cell lymphoma (MCL) as a model to characterize the mechanisms by which stroma regulate cell-cycle progression. We demonstrated that adhesion of MCL and other non-Hodgkin lymphoma (NHL) cells to bone marrow stroma cell (HS-5) resulted in a reversible G₁ arrest associated with elevated p27^Kip1 protein level. The adhesion mediated p27^Kip1 increase was posttranslational and regulated through down-regulating Skp2, a substrate-recognition subunit of SCF^Skp2 ubiquitin ligase. Overexpression of wild-type Skp2 in MCL decreases p27^Kip1, whereas inhibition of Skp2 expression by siRNA increases p27^Kip1 level. Furthermore, we found that cell adhesion up-regulated Cdh1, an activating subunit of anaphase-promoting complex (APC) ubiquitin ligase, and reducing Cdh1 by siRNA induced Skp2 accumulation and hence p27^Kip1 degradation, implicating Cdh1 as an upstream effector of Skp2/p27^Kip1 signaling pathway. Overall, this is a first report demonstrating that the bone marrow stroma controls tumor cell cycle via ubiquitin-proteasome proteolytic pathways in MCL and other NHL. The understanding of this novel molecular pathway may prove valuable in designing new therapeutic approaches modifying tumor cell growth and response to therapy.