Antineoplastic effects of 15(S)-hydroxyeicosatetraenoic acid and 13-S-hydroxyoctadecadienoic acid in non-small cell lung cancer.
BACKGROUND
Previous studies have shown that the levels of 15-lipoxygenase 1 (15-LOX-1) and 15-LOX-2 as well as their metabolites 13-S-hydroxyoctadecadienoic acid (13(S)-HODE) and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) are significantly reduced in smokers with non-small cell lung carcinoma (NSCLC). Furthermore, animal model experiments have indicated that the reduction of these molecules occurs before the establishment of cigarette smoking carcinogen-induced lung tumors, and this suggests roles in lung tumorigenesis. However, the functions of these molecules remain unknown in NSCLC.


METHODS
NSCLC cells were treated with exogenous 13(S)-HODE and 15(S)-HETE, and then the ways in which they affected cell function were examined. 15-LOX-1 and 15-LOX-2 were also overexpressed in tumor cells to restore these 2 enzymes to generate endogenous 13(S)-HODE and 15(S)-HETE before cell function was assessed.


RESULTS
The application of exogenous 13(S)-HODE and 15(S)-HETE significantly enhanced the activity of peroxisome proliferator-activated receptor γ (PPARγ), inhibited cell proliferation, induced apoptosis, and activated caspases 9 and 3. The overexpression of 15-LOX-1 and 15-LOX-2 obviously promoted the endogenous levels of 13(S)-HODE and 15(S)-HETE, which were demonstrated to be more effective in the inhibition of NSCLC.


CONCLUSIONS
This study has demonstrated that exogenous or endogenous 13(S)-HODE and 15(S)-HETE can functionally inhibit NSCLC, likely by activating PPARγ. The restoration of 15-LOX activity to increase the production of endogenous 15(S)-HETE and 13(S)-HODE may offer a novel research direction for molecular targeting treatment of smoking-related NSCLC. This strategy can potentially avoid side effects associated with the application of synthetic PPARγ ligands.
Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, People's Republic of China.
Ming-Yue
MY
Li
Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, People's Republic of China.|Department of Breast Surgery, Dongguan People's Hospital, Dongguan, People's Republic of China.
Hui-Ling
HL
Yuan
Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, People's Republic of China.
Fanny W S
FW
Ko
Department of Respiratory Medicine, Affiliated Hospital of Guang Dong Medical College, Zhanjiang, People's Republic of China.
Bin
B
Wu
Shenzhen Hospital, Peking University, Shenzhen, People's Republic of China.
Xiang
X
Long
Shenzhen Hospital, Peking University, Shenzhen, People's Republic of China.
Jing
J
Du
Department of Respiratory Medicine, Affiliated Hospital of Guang Dong Medical College, Zhanjiang, People's Republic of China.
Jun
J
Wu
Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, People's Republic of China.
Calvin S H
CS
Ng
Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, People's Republic of China.
Innes Y P
IY
Wan
Department of Clinical Oncology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, People's Republic of China.
Tony S K
TS
Mok
Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, People's Republic of China.
David S C
DS
Hui
Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, People's Republic of China.
Malcolm J
MJ
Underwood
Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, People's Republic of China.
George G
GG
Chen
D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000008:administration & dosage*; D047495:PPAR gamma / Q000235:genetics
D000970:Antineoplastic Agents; D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D047495:PPAR gamma; C495366:hydroxyoctadecadienoic acid; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase
13-S-hydroxyoctadecadienoic acid (13(S)-HODE); 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE); 15-lipoxygenase 1 (15-LOX-1); 15-lipoxygenase 2 (15-LOX-2); lung cancer; peroxisome proliferator-activated receptor γ (PPARγ)