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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4373-4384.
Prepublished online as a Blood First Edition Paper on September 4, 2007; DOI 10.1182/blood-2006-07-038026.
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NEOPLASIA
Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPAR cross talk with NF- B and C/EBPβ
Li Hua Wang1,2,
Xiao Yi Yang1,
Xiaohu Zhang1, and
William L. Farrar2
1 Basic Research Program, SAIC-Frederick, and
2 Cancer Stem Cell Section, Laboratory of Cancer Prevention, National Cancer Institute at Frederick, Frederick, MD
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  (PPAR) and its ligands can potently inhibit IL-6–regulated MM cell growth. Here we demonstrate that PPAR 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-dependent mechanism. The synthetic and natural PPAR agonists have diverging and overlapping mechanisms blocking transactivation of transcription factors NF- B and 5'-CCAAT/enhancer–binding protein β (C/EBPβ). Both 15-d-PGJ2 and troglitazone blocked C/EBPβ transcriptional activity by forming PPAR complexes with C/EBPβ. 15-d-PGJ2 and troglitazone also blocked NF-B activation by recruiting the coactivator PGC-1 from p65/p50 complexes. In addition, 15-d-PGJ2 had a non–PPAR-dependent effect by inactivation of phosphorylation of IKK and IB. These studies provide the framework for PPAR-based pharmacological strategies targeting adhesive interactions of MM cells with the bone marrow microenvironment.
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