Prostaglandins and cancer

Abstract

Prostaglandins (PGs) are lipids produced enzymatically and nonenzymatically from 20 carbon fatty acids, particularly arachidonic acid. Prostaglandins and related metabolites (collectively referred to as eicosanoids), including the thromboxanes, prostacyclins, hydroperoxy and hydroxy fatty acids, and leukotrienes are produced by most tissues of the body by oxidation of arachidonic acid, although the amount and class of product varies with cell type. The biological action of many of these eicosanoids as key regulators of cell processes that range from proliferation to adhesion and migration are currently being elucidated. An association of high levels of PGs and their synthetic enzymes, the PG synthases/cyclooxygenases, have been noted for many of the major types of cancer. Prostaglandins may contribute to the cancer processes through one or more of several mechanisms including increased proliferation, apoptosis, enhanced carcinogen metabolism or modulation of the immune system. The recent understanding of the regulation of substrate availability and of the regulation (or dysregulation in many neoplasias) of the synthetic enzymes has opened avenues leading to the design of isozyme specific inhibitors and better cancer prevention strategies. However, the apoptosis caused by these inhibitors as well as other drugs has raised some question concerning the relative importance of PGs. This is an issue that remains to be resolved.

Prostaglandin E2 regulates melanocyte dendrite formation through activation of PKCζ

“…Melanocyte dendrites are important for prevention of cutaneous cancers because of the requirement for dendrites in the transfer of photoprotective pigment-laden melanosomes to keratinocytes. We identified the expression of two of the four EP receptors for PGE 2 on melanocytes in vitro (EP 1 and EP 3 ) and showed that signaling by these receptors could independently stimulate the formation of dendrites in melanocytes [7]. Prior reports have shown that the EP 3 receptor is expressed in the basal epidermal layer, where melanocytes reside [40] and our data shows that human melanocytes express EP 3 in vivo.…”

“…The effects of prostaglandins and the cross talk between prostaglandin receptors and their signaling intermediates are of intense interest because of the diverse effects of prostaglandins on cell growth, differentiation and carcinogenesis [3,38,[41][42][43]. While the effects of PGE 2 on epidermal keratinocytes are reasonably well understood [1,[43][44][45], there has been much less investigation in the effects of PGE 2 on human melanocytes.…”

“…Melanocytes were treated with the EP 1 agonist 17-PT PGE 2 (25 nM) or the EP 3 agonist misoprostol (500 nM) for time points ranging from 5 to 45 minutes, and total cell lysates were blotted for P-PKCζ (Figure 2A). The Ki (nM) of 17-PT for the EP 1 and EP 3 receptors are 7.3 nM and 80 nM respectively [32,34]; the Ki of misoprostol for the EP 3 and EP 1 receptors are 319 nM and 38,000 nM respectively [34]. The levels of P-PKCζ in untreated melanocytes varied from culture to culture, however, consistent phosphorylation of PKCζ in response to both 17-PT PGE 2 and misoprostol was detected.…”

“…In the epidermis, PGE 2 is the main prostaglandin produced by keratinocytes in response to ultraviolet irradiation (UVR), and mediates multiple cellular functions including immune regulation, cell growth and differentiation, and carcinogenesis [1][2][3][4]. PGE 2 mediates its effects through 4 G-protein coupled receptors (EP 1 -EP 4 ) that are expressed in a cell-type specific fashion and activate diverse signaling intermediates [5,6].…”

“…The EP 1 receptor is a low affinity receptor for PGE 2 that couples to G q to activate phospholipase C [8,9] and raises intracellular calcium. The EP 3 receptor, unlike the other PGE 2 receptors, has multiple isoforms (8 in human and 3 in mice) and couples to multiple small G-proteins, including G(i) (inhibition of adenylate cyclase), G βγ (increase in intracellular Ca +2 ) and G 13 (activation of the small G protein Rho [10]). …”