An antitumorigenic role for murine 8S-lipoxygenase in skin carcinogenesis

Abstract

The levels of 8S-lipoxygenase (8S-LOX) expression and of its arachidonic acid metabolite, 8-hydroxyeicosatetraenoic acid (8-HETE), are highly elevated in the early stages of mouse skin carcinogenesis. On the other hand, several reports showing that 8-HETE is also closely associated with keratinocyte differentiation raise a question concerning the role of 8S-LOX/8-HETE in skin carcinogenesis. To address that question, here we conducted a series of gain-of-function studies. Skin targeted loricrin 8S-LOX/C57BL/6J transgenic mice showed a more differentiated epidermal phenotype as well as a 64% reduced papilloma development in a two-stage skin carcinogenesis protocol. Forced expression of 8S-LOX in MT1/2 cells, a murine papilloma cell line, also caused a more differentiated appearance as well as keratin 1 expression. Overexpression of 8S-LOX in CH72 cells, a murine carcinoma cell line, inhibited cell proliferation by 30% in vitro and by 86% in in vivo xenografts. Exogenous addition of 5 lM 8-HETE to CH72 cells caused cell cycle arrest at the G1 phase. Finally, immunohistochemical analyses showed 8S-LOX protein expression was strictly confined to the differentiated compartment of mouse skin and throughout tumorigenesis. Collectively, these data suggest that 8S-LOX plays a role as a prodifferentiating, antitumorigenic, and tumor suppressing gene in mouse skin carcinogenesis.

Inducible expression of 15-lipoxygenase-2 and 8-lipoxygenase inhibits cell growth via common signaling pathways

“…We chose an inducible expression system because neither primary keratinocytes nor nontumorigenic keratinocytes retained the capacity to grow when 8-LOX or 15-LOX-2 was stably expressed. This holds true for 308 keratinocytes (data not shown) and another papilloma cell line, MT1/2, carrying the 8-LOX transgene, which decreased growth and lost the transgene after two to three passages (32). As shown here, the induction of either 8-LOX or 15-LOX-2 did indeed decrease the growth rate in both expression lines compared with parental 308 and Cl20 control cells.…”

“…Such an effect was observed in human prostatic epithelial cells upon ectopic expression of 15-LOX-2 (24). Forced expression of 8-LOX in CH72 carcinoma cells was previously found to reduce the growth capacity of the stable transfectants, an effect that was attributed to a G1 block (32). This was not observed in 308 cells upon induction of either 8-LOX or 15-LOX-2 expression.…”

Human and mouse eLOX3 have distinct substrate specificities: Implications for their linkage with lipoxygenases in skin

“…Notably, the role of 8-LOX in murine epidermal differentiation can at least partly be explained by the biological activity of 8S-HETE, which can account for some of the pro-differentiating effects observed upon 8S-LOX overexpression [26,27]. An equivalent biological activity of the hepoxilin products remains to be demonstrated.…”

What are cyclooxygenases and lipoxygenases doing in the driver's seat of carcinogenesis?

“…This view is supported by experimental studies showing that the forced expression of 8-LOX or the induced expression of l12S-LOX reduced DMBA/ TPA-induced skin tumor formation in transgenic mice. 48,49 In this context, it is intriguing that high doses of COX inhibitors were shown to induce the expression of 15-LOX-1 in a COX-independent manner in vitro and that this effect may contribute to the antitumor activities of COX inhibitors. 50 In the prostate, however, the human ortholog 15-LOX-1 was found to exhibit a protumorigenic activity as its expression was increased in prostate cancer and 15-LOX-1 overexpressing prostate cells showed increased tumor progression when injected in nude mice.…”