Platelet-type 12-lipoxygenase accelerates tumor promotion of mouse epidermal cells through enhancement of cloning efficiency.
Accumulating evidence suggests that platelet-type 12-lipoxygenase (p12-LOX) plays an important role in tumor development. However, how p12-LOX contributes to tumorigenesis is still not understood. The role of p12-LOX was therefore examined in tumor promotion using mouse epidermal JB6 P+ cells that are sensitive to 12-O-tetradecanoylphorbol-13-acetate-induced transformation. The expression of p12-LOX was significantly higher in JB6 P+ cells than in JB6 P- cells that were resistant to transformation, and its expression was further increased by tumor necrosis factor (TNF)-alpha. Importantly, the inhibition of p12-LOX in JB6 P+ cells by baicalein, a specific inhibitor or small interfering RNA significantly suppressed TPA-induced transformation. Moreover, treatment with 12(S)-hydroxyeicosatetraenoic acid (HETE), a metabolite of p12-LOX, enhanced TPA-induced neoplastic transformation either in the presence or absence of baicalein. These results indicate that p12-LOX is required for tumor promotion of epidermal cells and that 12(S)-HETE functions as a rate-limiting factor. Notably, treatment with baicalein significantly suppressed the proliferation of JB6 P+ cells when cells were seeded at a low density in a culture plate. Moreover, the cloning efficiency of JB6 P+ cells was dramatically decreased by inhibition of p12-LOX. In contrast, baicalein treatment did not affect the cloning efficiency of most malignant cancer cells. These results indicate that p12-LOX is induced by the inflammatory cytokine TNF-alpha in the early stage of tumorigenesis, and is required for tumor promotion through enhancing efficient proliferation of a small number of initiated cells. The present results suggest that the p12-LOX pathway may be an effective target of chemoprevention for skin carcinogenesis.
Piao
Ying-Shi
YS
Division of Genetics, Cancer Research Institute, Graduate School of Medicine, Kanazawa University, Kanazawa 920-0934, Japan.
Du
Yu-Chen
YC
Oshima
Hiroko
H
Jin
Jing-Chun
JC
Nomura
Masaaki
M
Yoshimoto
Tanihiro
T
Oshima
Masanobu
M
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000494:pharmacology; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000097:blood*; D001792:Blood Platelets / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004817:Epidermis / Q000473:pathology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D044950:Flavanones / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D012878:Skin Neoplasms / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004791:Enzyme Inhibitors; D044950:Flavanones; D014409:Tumor Necrosis Factor-alpha; C006680:baicalein; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase