Over 80% of the lung cancer patients have non-small cell lung cancer (NSCLC). Although the anticancer mechanisms of omega-3 polyunsaturated fatty acids (≥3-PUFAs) have been reported in several cancers, it is still unclear in lung cancer. In this study, we have identified a novel anticancer effect of docosahexaenoic acid (DHA), a α3-PUFAs, on NSCLC. DHA induced cytotoxicity and morphology change in A549 and H1299 NSCLC cells and was confirmed that apoptosis and autophagy are responsible for the cytotoxicity induced by DHA. DHA increased AMPK activity and inhibited PI3K/Akt signaling as well as mTOR signaling molecules. Knockdown AMPK using small interfering RNAs specific for AMPK and overexpression Akt significantly enhanced the mTOR activity and attenuated the cell death caused by DHA treatment, indicating that DHA induces NSCLC cell death via the AMPK- and Akt-regulated mTOR inactivation. We also confirmed this effect of α3-PUFAs in vivo using Fat-1 transgenic mice that are capable of producing α3-PUFAs. When mouse lung cancer LLC cells were subcutaneously implanted into Fat-1 mice, the growth of tumor was markedly inhibited with decrease the level of p-Akt as well as increases in TUNEL-positive staining cells and autophagic levels, compared to wild-type mice. Taken together, these data suggest that the apoptosis and autophagy induced by DHA may be related to mTOR inhibition through AMPK activation and PI3K/Akt inhibition in NSCLC. Therefore, utilization of DHA may represent a potential effective therapy for the chemoprevention and treatment of human non-small cell lung cancer. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (2011-0013263 and 2011-0006232)]

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2274. doi:1538-7445.AM2012-2274