The cyclopentenone 15-deoxy-delta(12,14)-prostaglandin J2 inhibits G1/S transition and retinoblastoma protein phosphorylation in immortalized lymphocytes from Alzheimer's disease patients.
Epidemiologic studies indicated that non-steroidal anti-inflammatory drugs (NSAIDs) might prevent or delay the clinical features of Alzheimer disease (AD). The pharmacological activity of NSAIDs is generally attributed to inhibition of cyclooxygenase and peroxisome proliferator-activated receptor gamma (PPARgamma) activation. Based on the antineoplastic and apoptotic effects of PPARgamma activation in a number of cell types, we hypothesized that NSAIDs could protect neurons by controlling the regulation of cell cycle. Recent work suggests that uncoordinated expression of cell cycle molecules and perturbation of cell cycle checkpoints may be one of the mechanisms by which post-mitotic neurons die. Since cell cycle dysfunction is not restricted to neurons in AD, we found it interesting to study the role of PPARgamma activation on cell proliferation in immortalized lymphocytes from AD patients. We report here that 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2), but not NSAIDs or thiazolidinediones inhibited the serum-mediated enhancement of cell proliferation in AD by blocking the events critical for G1/S transition. The cyclopentenone induced a partial inhibition of retinoblastoma protein phosphorylation and increased levels of the CDK inhibitor p27kip1.
Muñoz
Ursula
U
Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040-Madrid, Spain.
de Las Cuevas
Natividad
N
Bartolomé
Fernando
F
Hermida
Ofelia G
OG
Bermejo
Félix
F
Martín-Requero
Angeles
A
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects; D016022:Case-Control Studies; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects; D008297:Male; D047495:PPAR gamma / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism*; D013997:Time Factors
C477819:15-deoxyprostaglandin J2; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D016160:Retinoblastoma Protein; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D015230:Prostaglandin D2