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

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 gamma (PPAR gamma) and its ligands can potently inhibit IL-6-regulated MM cell growth. Here we demonstrate that PPAR gamma 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 PPAR gamma-dependent mechanism. The synthetic and natural PPAR gamma agonists have diverging and overlapping mechanisms blocking transactivation of transcription factors NF-kappa B and 5'-CCAAT/enhancer-binding protein beta (C/EBP beta). Both 15-d-PGJ2 and troglilazone blocked C/EBP beta transcriptional activity by forming PPAR gamma complexes with C/EBP beta. 15-d-PGJ2 and trogiltazone also blocked NF-kappa B activation by recruiting the coactivator PGC-1 from p65/ p50 complexes. In addition, 15-d-PGJ2 had a non-PPAR gamma-dependent effect by inactivation of phosphorylation of IKK and I kappa B. These studies provide the framework for PPAR gamma-based pharmacological strategies targeting adhesive interactions of MM cells with the bone marrow microenvironment.