Phenylbutyrate induces apoptosis and lipid accumulations via a peroxisome proliferator-activated receptor gamma-dependent pathway.
The effects of the selective peroxisome proliferator activated receptor-gamma (PPAR-gamma) inhibitor GW9662 on phenylbutyrate (PB)-induced NMR-detectable lipid metabolites was investigated on DU145 prostate cancer cells. DU145 cells were perfused with 10 mM PB in the presence or absence of 1 microM of GW9662 and the results monitored by (31)P and diffusion-weighted (1)H NMR spectroscopy. GW9662 completely reversed PB-induced NMR-visible lipid and total choline accumulation in (1)H spectra and glycerophosphocholine and beta-NTP in (31)P spectra. In addition, pre-incubation with GW9662 significantly reduced PB-induced caspase-3 activation, reversed the G(1) block as measured by flow cytometry, and otherwise had little effect on cell survival as measured by MTT assay. These results suggest that the NMR visible lipid accumulation and apoptosis induced by PB treatment occurs through a mechanism that is mediated by PPAR-gamma.
Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Matthew
M
Milkevitch
Nancy J
NJ
Beardsley
E James
EJ
Delikatny
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism; D038524:Diffusion Magnetic Resonance Imaging; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D047495:PPAR gamma / Q000378:metabolism*; D010654:Phenylbutyrates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D004273:DNA, Neoplasm; D047495:PPAR gamma; D010654:Phenylbutyrates; D053148:Caspase 3