Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPARγ cross talk with NF-κB and C/EBPβ

Abstract

Binding of multiple myeloma (MM) cells to bone marrow stromal cells (BMSCs) triggers expression of adhesive molecules and secretion of interleukin-6 (IL-6), promoting MM cell growth, survival, drug resistance, and migration, which highlights the possibility of developing and validating novel anti-MM therapeutic strategies targeting MM cells–host BMSC interactions and their sequelae. Recently, we have found that expression of the peroxisome proliferator-activated receptor γ (PPARγ) and its ligands can potently inhibit IL-6–regulated MM cell growth. Here we demonstrate that PPARγ agonists 15-d-PGJ2 and troglitazone significantly suppress cell-cell adhesive events, including expression of adhesion molecules and IL-6 secretion from BMSCs triggered by adhesion of MM cells, as well as overcome drug resistance by a PPARγ-dependent mechanism. The synthetic and natural PPARγ agonists have diverging and overlapping mechanisms blocking transactivation of transcription factors NF-κB and 5′-CCAAT/enhancer–binding protein β (C/EBPβ). Both 15-d-PGJ2 and troglitazone blocked C/EBPβ transcriptional activity by forming PPARγ complexes with C/EBPβ. 15-d-PGJ2 and troglitazone also blocked NF-κB activation by recruiting the coactivator PGC-1 from p65/p50 complexes. In addition, 15-d-PGJ2 had a non–PPARγ-dependent effect by inactivation of phosphorylation of IKK and IκB. These studies provide the framework for PPARγ-based pharmacological strategies targeting adhesive interactions of MM cells with the bone marrow microenvironment.