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

Purpose: Peroxisome proliferator-activated receptor gamma (PPAR-gamma) 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 gamma. Moreover, certain PPAR-gamma ligands can induce apoptosis in multiple myeloma cells. Because PPAR-gamma ligands can also have PPAR gamma-independent effects, the role of PPAR gamma in B-cell malignancies remains poorly understood. To further understand the role of PPAR gamma, 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 gamma gene delivery. We transduced multiple myeloma cells with a lentivirus-expressing PPAR gamma 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 gamma-overexpressing cells were dramatically more sensitive to PPAR gamma 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 gamma 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 gamma overexpression in multiple myeloma or BMSC inhibited both basal and multiple myeloma-induced interleukin-6 production by BMSC. Conclusions: Our results indicate that PPAR gamma negatively controls multiple myeloma growth and viability in part through inhibition of interleukin-6 production by BMSC. As such, PPAR gamma is a viable therapeutic target in multiple myeloma.