Docosahexaenoic Acid Induces Cell Death in Human Non-Small Cell Lung Cancer Cells by Repressing mTOR via AMPK Activation and PI3K/Akt Inhibition

Abstract

The anticancer properties and mechanism of action of omega-3 polyunsaturated fatty acids (ω3-PUFAs) have been demonstrated in several cancers; however, the mechanism in lung cancer remains unclear. Here, we show that docosahexaenoic acid (DHA), a ω3-PUFA, induced apoptosis and autophagy in non-small cell lung cancer (NSCLC) cells. DHA-induced cell death was accompanied by AMP-activated protein kinase (AMPK) activation and inactivated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling. Knocking down AMPK and overexpressing Akt increased mTOR activity and attenuated DHA-induced cell death, suggesting that DHA induces cell death via AMPK- and Akt-regulated mTOR inactivation. This was confirmed in Fat-1 transgenic mice, which produce ω3-PUFAs. Lewis lung cancer (LLC) tumor cells implanted into Fat-1 mice showed slower growth, lower phospho-Akt levels, and higher levels of apoptosis and autophagy than cells implanted into wild-type mice. Taken together, these data suggest that DHA-induced apoptosis and autophagy in NSCLC cells are associated with AMPK activation and PI3K/Akt inhibition, which in turn lead to suppression of mTOR; thus ω3-PUFAs may be utilized as potential therapeutic agents for NSCLC treatment.

Toxic effects of n-3 polyunsaturated fatty acids in human lung A549 cells

“…However the ROS-mediated Akt-mTOR signaling inactivation may be responsible for autophagy and apoptosis induced by DHA also in cancer cells expressing altered p53 (Shin et al, 2013). Recently, Kim et al (2014) have documented that DHA-induced apoptosis and autophagy in non-small cell lung cancer cells are associated with AMPK activation and PI3K/Akt inhibition, which in turn lead to the suppression of mTOR.…”

Preparation of coffee oil-algae oil-based nanoemulsions and the study of their inhibition effect on UVA-induced skin damage in mice and melanoma cell growth

“…In contrast, in a study dealing with the effect of DHA standard on the inhibition of melanoma cells A-375, the IC 50 was 160 µM, 41 which was much higher than the IC 50 shown in our study (80.67 µM), demonstrating a higher inhibition efficiency of the coffee oil-algae oil nanoemulsion. For some other types of cancer cells, Kim et al 42 studied the effect of DHA standard (10-60 µM) on the growth of lung cancer cells H1299 and A549; a dose-dependent decrease in cell viability was observed with the IC 50 being 46 and 40 µM, respectively. Similarly, the IC 50 was 50 and 9.7 µM, respectively, after the treatment of lung cancer cells H1299 and A549 with DHA standard (1-100 µM) 43 and was 162.5 µM for liver cancer cells MHCC97L when treated with DHA standard (0-200 µM).…”

Alterative Expression and Localization of Profilin 1/VASPpS157 and Cofilin 1/VASPpS239 Regulates Metastatic Growth and Is Modified by DHA Supplementation

“…DHA has been and is currently being investigated as a potential therapeutic for cancer. Kim et al and Jing et al demonstrated that DHA induced apoptosis and autophagy in cancer cells through AMPK activation and PI3K/Akt inhibition, which led to suppression of mTOR signaling pathways (42, 43). Others have identified DHA-mediated changes in caspase 3 or disruptions in tumor suppressor expression (44).…”