Peroxisome proliferator activator receptor-gamma agonists and 15-deoxy-Delta(12,14)(12,14)-PGJ(2) induce apoptosis in normal and malignant B-lineage cells.
The research described herein evaluates the expression and functional significance of peroxisome proliferator activator receptor-gamma (PPAR-gamma) 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-gamma mRNA and, by Western blot analysis, the 67-kDa PPAR-gamma protein. 15-Deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), a PPAR-gamma agonist, has a dose-dependent antiproliferative and cytotoxic effect on normal and malignant B cells as shown by [(3)H]thymidine and 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide assays. Only PPAR-gamma agonists (thiazolidinediones), and not PPAR-alpha agonists, mimicked the effect of 15d-PGJ(2) on B-lineage cells, indicating that the mechanism by which 15d-PGJ(2) negatively affects B-lineage cells involves in part PPAR-gamma. The mechanism by which PPAR-gamma 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 PGF(2alpha), which was not known to affect lymphocytes, dramatically attenuated the deleterious effects of PPAR-gamma agonists on B lymphomas. Surprisingly, 15d-PGJ(2) induced a massive increase in nuclear mitogen-activated protein kinase activation, and pretreatment with PGF(2alpha) blunted the mitogen-activated protein kinase activation. This is the first study evaluating PPAR-gamma expression and its significance on B lymphocytes. PPAR-gamma agonists may serve as a counterbalance to the stimulating effects of other PGs, namely PGE(2), which promotes B cell differentiation. Finally, the use of PGs, such as 15d-PGJ(2), and synthetic PPAR-gamma agonists to induce apoptosis in B-lineage cells may lead to the development of novel therapies for fatal B lymphomas.
Padilla
J
J
University of Rochester Cancer Center and Departments of Microbiology and Immunology, Pediatrics, Environmental Medicine, and Periodontology, Eastman Department of Dentistry, Rochester, NY 14642, USA.
Kaur
K
K
Cao
H J
HJ
Smith
T J
TJ
Phipps
R P
RP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019070:Cell Lineage / Q000276:immunology; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000502:physiology* / Q000633:toxicity; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002839:Chromans; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D015237:Dinoprost; D000077288:Troglitazone; D015230:Prostaglandin D2; C039671:ciglitazone