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Peroxisome Proliferator-Activated Receptor Overexpression Suppresses Growth and Induces Apoptosis in Human Multiple Myeloma Cells

Authors' Affiliations: Departments of ¹ Microbiology and Immunology and ² Environmental Medicine, ³ Lung Biology and Disease Program, and ⁴ The Lymphoma Biology Program of the James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York

Requests for reprints: Richard P. Phipps, Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 850, Rochester, NY 14642. Phone: 585-275-8326; Fax: 585-506-0239; E-mail: Richard_Phipps{at}urmc.rochester.edu.

Purpose: Peroxisome proliferator-activated receptor (PPAR) is a transcription factor that regulates immune and inflammatory responses. Our laboratory has shown that normal and malignant B cells, including multiple myeloma, express PPAR. Moreover, certain PPAR ligands can induce apoptosis in multiple myeloma cells. Because PPAR ligands can also have PPAR-independent effects, the role of PPAR in B-cell malignancies remains poorly understood. To further understand the role of PPAR, we examined the functional consequences of its overexpression in human multiple myeloma.

Experimental Design: In the present work, we developed a lentiviral vector for PPAR gene delivery. We transduced multiple myeloma cells with a lentivirus-expressing PPAR and studied the involvement of this receptor on cell growth and viability.

Results: PPAR overexpression decreased multiple myeloma cell proliferation and induced spontaneous apoptosis even in the absence of exogenous ligand. These PPAR-overexpressing cells were dramatically more sensitive to PPAR ligand-induced apoptosis compared with uninfected or LV-empty-infected cells. Apoptosis was associated with the down-regulation of antiapoptotic proteins X-linked inhibitor of apoptosis protein and myeloid cell leukemia-1 as well as induction of caspase-3 activity. Importantly, PPAR overexpression-induced cell death was not abrogated by coincubation with bone marrow stromal cells (BMSC), which are known to protect multiple myeloma cells from apoptosis. Additionally, PPAR overexpression in multiple myeloma or BMSC inhibited both basal and multiple myeloma-induced interleukin-6 production by BMSC.

Conclusions: Our results indicate that PPAR negatively controls multiple myeloma growth and viability in part through inhibition of interleukin-6 production by BMSC. As such, PPAR is a viable therapeutic target in multiple myeloma.