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Agonists and 15-Deoxy-
12,1412,14-PGJ2 Induce Apoptosis in Normal and Malignant B-Lineage Cells1
,¶,
,§
*
University of Rochester Cancer Center and Departments of
Microbiology and Immunology,
Pediatrics,
§
Environmental Medicine, and
¶
Periodontology, Eastman Department of Dentistry, Rochester, NY 14642; and
||
Division of Molecular Medicine, University of California, Los Angeles School of Medicine, Harbor-University of California Los Angeles Medical Center, Torrance, CA 90502
The research described herein evaluates the expression and
functional significance of peroxisome proliferator activator
receptor-
(PPAR-) on B-lineage cells. Normal mouse B cells and a
variety of B lymphoma cells reflective of stages of B cell
differentiation (e.g., 70Z/3, CH31, WEHI-231, CH12, and J558) express
PPAR- mRNA and, by Western blot analysis, the 67-kDa PPAR-
protein. 15-Deoxy-
12,14-PGJ2
(15d-PGJ2), a PPAR- agonist, has a dose-dependent
antiproliferative and cytotoxic effect on normal and malignant B cells
as shown by [3H]thymidine and
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays.
Only PPAR- agonists (thiazolidinediones), and not PPAR-
agonists,
mimicked the effect of 15d-PGJ2 on B-lineage cells,
indicating that the mechanism by which 15d-PGJ2 negatively
affects B-lineage cells involves in part PPAR-. The mechanism by
which PPAR- agonists induce cytotoxicity is via apoptosis, as shown
by annexin V staining and as confirmed by DNA fragmentation detected
using the TUNEL assay. Interestingly, addition of PGF2,
which was not known to affect lymphocytes, dramatically attenuated the
deleterious effects of PPAR- agonists on B lymphomas. Surprisingly,
15d-PGJ2 induced a massive increase in nuclear
mitogen-activated protein kinase activation, and pretreatment with
PGF2 blunted the mitogen-activated protein kinase
activation. This is the first study evaluating PPAR- expression and
its significance on B lymphocytes. PPAR- agonists may serve as a
counterbalance to the stimulating effects of other PGs, namely
PGE2, which promotes B cell differentiation. Finally, the
use of PGs, such as 15d-PGJ2, and synthetic PPAR-
agonists to induce apoptosis in B-lineage cells may lead to the
development of novel therapies for fatal B
lymphomas.
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