Cell cycle arrest by prostaglandin A₁ at the G₁/S phase interface with up‐regulation of oncogenes in S‐49 cyc⁻ cells

Abstract

Our previous studies have implied that prostaglandins inhibit cell growth independent of cAMP. Recent reports, however, have suggested that prostaglandin arrest of the cell cycle may be mediated through protein kinase A. In this report, in order to eliminate the role of c-AMP in prostaglandin mediated cell cycle arrest, we use the -49 lymphoma variant (cyc-) cells that lack adenylate cyclase activity. We demonstrate that dimethyl prostaglandin A1 (dmPGA1) inhibits DNA synthesis and cell growth in cyc- cells. DNA synthesis is inhibited 42% by dmPGA1 (50 microM) despite the fact that this cell line lacks cellular components needed for cAMP generation. The ability to decrease DNA synthesis depends upon the specific prostaglandin structure with the most effective form possessing the alpha, beta unsaturated ketone ring. Dimethyl PGA1 is most effective in inhibiting DNA synthesis in cyc- cells, with prostaglandins PGE1 and PGB1 being less potent inhibitors of DNA synthesis. DmPGE2 caused a significant stimulation of DNA synthesis. S-49 cyc- variant cells exposed to (30-50 microns) dmPGA1, arrested in the G1 phase of the cell cycle within 24 h. This growth arrest was reversed when the prostaglandin was removed from the cultured cells; growth resumed within hours showing that this treatment is not toxic. The S-49 cyc- cells were chosen not only for their lack of adenylate cyclase activity, but also because their cell cycle has been extensively studied and time requirements for G1, S, G2, and M phases are known. Within hours after prostaglandin removal the cells resume active DNA synthesis, and cell number doubles within 15 h suggesting rapid entry into S-phase DNA synthesis from the G1 cell cycle block.(ABSTRACT TRUNCATED AT 250 WORDS)

Down-Regulation of Cyclin D1 Expression by Prostaglandin A2 Is Mediated by Enhanced Cyclin D1 mRNA Turnover

“…Growth arrest following PGA 2 treatment occurs primarily in the G 1 phase of the cell cycle, but the mechanisms responsible for eliciting this effect are not well understood. Along with several growthregulatory genes whose expression is altered following treatment with PGA 2 or with related prostaglandins (2,24,27), we previously reported that PGA 2 -mediated growth inhibition was associated with a rapid and dramatic loss in cyclin D1 expression (20). Here, we have investigated the mechanisms contributing to this down-regulation.…”

Prostaglandin A2-mediated Stabilization of p21 mRNA through an ERK-dependent Pathway Requiring the RNA-binding Protein HuR

“…Several microarray-based studies have led to the identification of mRNAs whose transcription and/or steadystate levels are regulated by PGA 2 and other cyclopentenone PGs (2,44). We and others have previously reported several gene expression changes occurring during the PGA 2 -triggered stress response, including the inhibition of cyclin D1 levels and the potent up-regulation of p21 expression (36,45,(47)(48)(49). Further analysis of the PGA 2 -mediated down-regulation of cyclin D1 expression revealed that PGA 2 decreased the stability of the cyclin D1 mRNA, identified a specific 390-base 3Ј-UTR segment involved in cyclin D1 mRNA decay, and suggested a role for AUF1 in these destabilization events (49).…”

Inhibition of G1 Cyclin-Dependent Kinase Activity during Growth Arrest of Human Breast Carcinoma Cells by Prostaglandin A2

“…The cyclopentenone prostaglandins A 1 (PGA 1 ) and A 2 (PGA 2 ) are potent inhibitors of growth in cultured cells (49,50) and exhibit antitumor activity in vivo (10,21,22,39,50). Growth arrest following PGA 2 treatment occurs primarily through a block in cell cycle progression at the G 1 -to-S transition, but the mechanisms responsible for eliciting this effect are still largely unknown (19). A number of genes (1,18,34) show altered expression following PGA 2 treatment, but the relationship between such changes in gene expression and the initiation and/or maintenance of the growth arrested state is unclear.…”