The effect of inhibitors of arachidonic acid metabolism on proliferation and death of tumor cells

Abstract

The effect of inhibitors of arachidonic acid metabolism on proliferation and death of tumor P-388 cells in a broad concentration range was studied. Cell proliferation was estimated by the metaphase frequency and the proportion of cells in S phase; cell death was determined from lysis, staining of cells with trypan blue, nuclear damage, percentage of cells with subdiploid DNA and the type of DNA fragmentation. It was shown that low concentrations of phospholipase A P and lipoxygenase inhibitors stimulated the proliferation of P-388 cells. At higher concentrations, the inhibitors suppressed cell proliferation by blocking the G I -S transition and induced cell death of the apoptosis type. Indomethacin, an inhibitor of cyclooxygenase, did not initiate cell death, nor did it affect the proliferation of P-388 cells at concentrations of up to 10 W WM. z 1998 Federation of European Biochemical Societies.

Phosphorylation of p42/44MAPK by Various Signal Transduction Pathways Activates Cytosolic Phospholipase A2to Variable Degrees

“…cPLA 2 (lane 12). This remaining phosphorylation is most likely due to activated PKC, or a related or unrelated kinase, since these cannot be down-regulated.…”

“…cPLA 2 activity is regulated by both calcium and phosphorylation. Submicromolar concentrations of calcium are required for cPLA 2 to translocate from the cytosol toward phospholipid membranes that is mediated by its calcium-dependent phospholipid binding domain (8). cPLA 2 phosphorylation was found to occur on Ser-505 through a mitogen-activated protein kinase (MAPK) (see Ref.…”

“…MAPK has been shown to phosphorylate cPLA 2 (14) on Ser-505 (15), and for a full activation, cPLA 2 must also be phosphorylated on Ser-727 by a Mnk1-related protein kinase (16). p42 /44 MAPK was the first MAPK family member shown to phosphorylate cPLA 2 on Ser-505 (17), and phosphorylation of cPLA 2 has been correlated with p42/44 MAPK phosphorylation in many cell models (6,18).…”

“…Stimulation of cells by epidermal growth factor (EGF) results in the activation of cPLA 2 (19,20). Subsequently, it was reported that in EGF-activated Herc13 and Her14 fibroblasts cPLA 2 was phosphorylated, and this phosphorylation had to precede a rise in the intracellular calcium concentration for the enzyme to become maximal active (12,21).…”

Signaling and interplay mediated by phospholipases A2, C, and D in LA-N-1 cell nuclei

“…Also, interphase cells release arachidonic acid in response to agonists, and this release is strongly inhibited in mitotic cells [40]. The addition of cPLA 2 inhibitors suppresses proliferation of cells by inducing apoptosis [41]. Assays of cPLA 2 activities in various phases of the cell cycle indicate that cPLA 2 activity is high in mitosis, decreases afterwards, and is increased again in G1 and following the G1/S transition phases.…”