Mingyue Li1, Hui-Ling Yuan2,1, Fanny W.S. Ko3, Bin Wu4, Xiang Long5, Jing Du5, Jun Wu4, Calvin S.H. Ng1, Innes Y.P. Wan1, Tony Mok6, David S.C. Hui3, Malcolm J. Underwood1, George G. Chen1
1Department of Surgery Prince of Wales Hospital, Chinese University of Hong Kong Hong Kong People's Republic of China
2Department of Breast Surgery Dongguan People's Hospital Dongguan People's Republic of China
3Department of Medicine and Therapeutics Prince of Wales Hospital, Chinese University of Hong Kong Hong Kong People's Republic of China
4Department of Respiratory Medicine Affiliated Hospital of Guang Dong Medical College Zhanjiang People's Republic of China
5Shenzhen Hospital Peking University Shenzhen People's Republic of China
6Department of Clinical Oncology Prince of Wales Hospital, Chinese University of Hong Kong Hong Kong People's Republic of China
Tóm tắt
BACKGROUNDPrevious 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.METHODSNSCLC 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.RESULTSThe 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.CONCLUSIONSThis 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. Cancer 2015;121:3130‐45. © 2015 American Cancer Society.
