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

Nayeong Kim,Kyu Lim,Soyeon Shin,Kaipeng Jing,Gi-Ryang Kweon,Jun-Young Heo,Tong Wu,Soyeon Kim,Soyeon Jeong,Jong-Il Park,Seung-Kiel Park

doi:10.1155/2015/239764

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.

Highlights

Lung cancer is the main cause of cancer-related death worldwide
We describe for the first time that docosahexaenoic acid (DHA) triggers autophagy and apoptosis in non-small-cell lung cancer (NSCLC) cells, which simultaneously promotes cell death
Our results indicate that the DHA-induced autophagy and apoptosis are controlled by repressing mammalian target of rapamycin (mTOR) through AMPK activation and phosphatidylinositol 3-kinase (PI3K)/Akt inhibition (Figure 6)

Summary

Introduction

Lung cancer is the main cause of cancer-related death worldwide. Because NSCLC is much less sensitive to chemotherapy than SCLC [3], a new approach for treating NSCLC is required. Autophagy is a lysosome-associated degradation process that is characterized by the formation of double-membraned autophagosomes, which encapsulate cytoplasmic constituents [4,5,6]. The degraded components can be used for energy production and other cellular processes [7]. The most potent inhibitor of autophagy is mammalian target of rapamycin (mTOR), which acts upstream of Atg proteins to regulate cell growth/ proliferation, survival, protein and lipid synthesis, lysosome biogenesis, and cytoskeletal organization [10,11,12]. Inhibiting mTOR blocks the phosphorylation of S6K1 and 4E-BP1, and induces autophagy [16,17,18]

Methods

Results

Conclusion