Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPARgamma cross talk with NF-kappaB and C/EBP.
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 (PPARgamma) and its ligands can potently inhibit IL-6-regulated MM cell growth. Here we demonstrate that PPARgamma 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 PPARgamma-dependent mechanism. The synthetic and natural PPARgamma agonists have diverging and overlapping mechanisms blocking transactivation of transcription factors NF-kappaB and 5'-CCAAT/enhancer-binding protein beta (C/EBPbeta). Both 15-d-PGJ2 and troglitazone blocked C/EBPbeta transcriptional activity by forming PPARgamma complexes with C/EBPbeta. 15-d-PGJ2 and troglitazone also blocked NF-kappaB activation by recruiting the coactivator PGC-1 from p65/p50 complexes. In addition, 15-d-PGJ2 had a non-PPARgamma-dependent effect by inactivation of phosphorylation of IKK and IkappaB. These studies provide the framework for PPARgamma-based pharmacological strategies targeting adhesive interactions of MM cells with the bone marrow microenvironment.
Wang
Li Hua
LH
Basic Research Program, SAIC-Frederick, Frederick, MD, USA. lhwang@ncifcrf.gov
Yang
Xiao Yi
XY
Zhang
Xiaohu
X
Farrar
William L
WL
D001853:Bone Marrow; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D020239:Receptor Cross-Talk; D017154:Stromal Cells / Q000473:pathology*; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone