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 muM 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.

• Authors: Eunjung Kim, Joyce E Rundhaug, Fernando Benavides, Peiying Yang, Robert A Newman, Susan M Fischer
• Journal: Oncogene (Oncogene) Vol. 24 Issue 7 Pg. 1174-87 (Feb 10 2005) ISSN: 0950-9232 [Print] England
• PMID: 15558016 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Hydroxyeicosatetraenoic Acids
• Linoleic Acids, Conjugated
• Membrane Proteins
• RNA, Messenger
• loricrin
• 9-hydroxy-10,12-octadecadienoic acid
• 8-hydroxyeicosatetraenoic acid
• Arachidonate Lipoxygenases
• arachidonate 8-lipoxygenase
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Arachidonate Lipoxygenases (analysis, genetics, physiology)
• Carcinoma (etiology, genetics, metabolism)
• Cell Line
• Cell Proliferation
• Cell Transformation, Neoplastic (genetics, metabolism)
• Female
• Gene Expression (drug effects)
• Genes, Tumor Suppressor
• Hydroxyeicosatetraenoic Acids (biosynthesis, pharmacology)
• Linoleic Acids, Conjugated (biosynthesis, pharmacology)
• Membrane Proteins (genetics)
• Mice
• Mice, Transgenic
• Papilloma (etiology, genetics, metabolism)
• Promoter Regions, Genetic (genetics)
• RNA, Messenger (analysis, metabolism)
• Skin (drug effects, metabolism)
• Skin Neoplasms (etiology, genetics, metabolism)
• Tetradecanoylphorbol Acetate (pharmacology)
• Transgenes (genetics)