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

Clin Cancer Res. 2008 Oct 15;14(20):6414-25. doi: 10.1158/1078-0432.CCR-08-0457.

Abstract

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

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

Results: PPARgamma overexpression decreased multiple myeloma cell proliferation and induced spontaneous apoptosis even in the absence of exogenous ligand. These PPARgamma-overexpressing cells were dramatically more sensitive to PPARgamma 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, PPARgamma 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, PPARgamma overexpression in multiple myeloma or BMSC inhibited both basal and multiple myeloma-induced interleukin-6 production by BMSC.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Blotting, Western
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Caspases / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Interleukin-6 / metabolism
  • Lentivirus
  • Multiple Myeloma / pathology*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism
  • Thiazolidinediones / pharmacology
  • X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

  • Hypoglycemic Agents
  • Interleukin-6
  • PPAR gamma
  • Thiazolidinediones
  • X-Linked Inhibitor of Apoptosis Protein
  • Caspases
  • ciglitazone