The cyclopentenone 15-deoxy-Δ12,14-prostaglandin J2 inhibits G1/S transition and retinoblastoma protein phosphorylation in immortalized lymphocytes from Alzheimer's disease patients

Abstract

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.

On the mechanism of inhibition of p27 degradation by 15-deoxy-Δ12,14-prostaglandin J 2 in lymphoblasts of Alzheimer’s disease patients

“…Figure 1A shows a time course analysis of the effect of 15d-PGJ 2 on rates of proliferation of control and AD lymphoblasts following serum stimulation. It is shown, in agreement with previous results [28], that AD cells proliferate at a higher rate than control cells (Fig. 1A).…”

“…Effects of 15d-PGJ 2 on cell proliferation It was previously reported that 15d-PGJ 2 has an antiproliferative effect on lymphoblasts from AD patients associated with altered control of G 1 /S transition and accumulation of p27 protein [28]. For this reason, we first tried to elucidate the effects of 15d-PGJ 2 treatment on the phosphorylation status of the pRb and on the kinase activity of cyclin E/CDK2 complex, the key regulators of transition from G 1 phase of the cell cycle to S phase.…”

“…Based on these observations, we hypothesized that the protective effects of antiinflammatory drugs on AD progression could be related to their ability to regulate cell cycle events. It was reported that 15d-PGJ 2 is able to selectively blunt the serum-enhanced proliferation of immortalized lymphocytes from late-onset AD patients without affecting normal proliferative response of control cells [28]. 15d-PGJ 2 inhibits cell cycle progression at the G 1 / S checkpoint in AD lymphoblasts [28].…”

“…Effects of 15d-PGJ 2 preventing activation of PI3K/Akt and up-regulation of p27 protein are unlikely to be mediated by PPARg activation We previously reported [28] that the anti-proliferative effect of 15d-PGJ 2 in human lymphoblasts is not dependent on PPARg activation since it could not be blocked by the selective PPARg antagonist GW9662, and other PPARg ligands did not mimic the effect of 15d-PGJ 2 on proliferation of AD cells. Data in Figure 9 confirm and extend our previous finding, by showing that cell proliferation (Fig.…”

“…These observations indicate that established lymphoblastoid cell lines could be a suitable model to study the influence of cell cycle-related events in the pathogenesis of AD. We have previously reported that 15d-PGJ 2 inhibited the serum-enhanced cell proliferation of lymphoblasts from AD patients, by blocking the critical events for G 1 /S transition [28]. The cyclopentenone partially inhibited phosphorylation of retinoblastoma protein (pRb) and up-regulated the levels of the cyclindependent kinase (CDK) inhibitor p27.…”