15-Lipoxygenases and its metabolites 15(S)-HETE and 13(S)-HODE in the development of non-small cell lung cancer.
BACKGROUND
15-S-Hydroxyeicosatetraenoic acid (15(S)-HETE) and 13-S-hydroxyoctadecadienoic acid (13(S)-HODE), both of which are metabolites of 15-lipoxygenases (15-LOXs), are endogenous ligands for peroxisome proliferator-activated receptor gamma (PPARgamma). The activation of PPARgamma inhibits cell growth and induces apoptosis in some cancers. The role of 15(S)-HETE) and 13(S)-HODE in the development of lung cancer is not clear.


METHODS
15-LOXs, 15(S)-HETE and 13(S)-HODE were monitored during the development of mouse lung tumours induced by the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and the levels of these markers were determined in 54 human non-small cell lung cancers.


RESULTS
15-LOXs, 15(S)-HETE and 13(S)-HODE levels were significantly reduced in human lung cancer tissue compared with non-tumour lung tissue (p=0.011 and p=0.022, respectively). In mouse experiments, 15(S)-HETE and 13(S)-HODE started to reduce at 26 and 30 weeks, respectively, after NNK treatment. The time frame of 15(S)-HETE reduction was in line with the decrease in 12/15-LOX mRNA and protein. A significant difference in the number of tumours in NNK-treated mice and controls was not observed until week 34 (p<0.05) and week 38 (p<0.01). The reduction in 12/15-LOX and 15(S)-HETE therefore predated the appearance of lung tumour. Furthermore, PPARgamma activity was decreased in NNK-treated mouse lungs compared with the control, and the decreased PPARgamma activity occurred at the same time points as the reduction in 12/15-LOX and 15(S)-HETE.


CONCLUSIONS
These findings indicate that the reduction in 15-LOX, 15(S)-HETE and 13(S)-HODE results in the decreased PPARgamma activity seen in lung tumours and contributes to the development of lung tumours induced by tobacco smoking.
Yuan
Huiling
H
Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.
Li
Ming-Yue
MY
Ma
Lily T
LT
Hsin
Michael K Y
MK
Mok
Tony S K
TS
Underwood
Malcolm J
MJ
Chen
George G
GG
D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D008041:Linoleic Acids / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D008805:Mice, Inbred A; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009602:Nitrosamines; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics
D014408:Biomarkers, Tumor; D006893:Hydroxyeicosatetraenoic Acids; D008041:Linoleic Acids; D009363:Neoplasm Proteins; D009602:Nitrosamines; D047495:PPAR gamma; C024348:13-hydroxy-9,11-octadecadienoic acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D001093:Arachidonate 15-Lipoxygenase