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

Kim N, Jeong S, Jing K, Shin S, Kim S, Heo JY, Kweon GR, Park SK, Wu T, Park JI, Lim K - Biomed Res Int (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea ; Infection Signaling Network Research Center, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.

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.

No MeSH data available.


Related in: MedlinePlus

DHA-induced autophagy is required for apoptotic cell death. The indicated cancer cell lines were treated with nontargeting control small interfering RNA (siNC) or siRNAs specific for autophagy-related Atg5 (a) and Atg7 (b). At 18 h after transfection, cells were incubated with the indicated doses of DHA for 24 h. Next, cells were harvested and subjected to western blot analysis with the following antibodies: Atg5, Atg7, LC3-II, and actin (upper panel). Cell viability was measured in an MTT assay (lower panel). ∗∗P < 0.01 and ∗∗∗P < 0.001. Data are representative of three independent experiments, all with similar results.
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fig3: DHA-induced autophagy is required for apoptotic cell death. The indicated cancer cell lines were treated with nontargeting control small interfering RNA (siNC) or siRNAs specific for autophagy-related Atg5 (a) and Atg7 (b). At 18 h after transfection, cells were incubated with the indicated doses of DHA for 24 h. Next, cells were harvested and subjected to western blot analysis with the following antibodies: Atg5, Atg7, LC3-II, and actin (upper panel). Cell viability was measured in an MTT assay (lower panel). ∗∗P < 0.01 and ∗∗∗P < 0.001. Data are representative of three independent experiments, all with similar results.

Mentions: To unveil the relationship between DHA-autophagy and DHA-apoptotic cell death, we used siRNAs to knock down two essential autophagy gene products, Atg5 and Atg7. Although silencing of Atg5 and Atg7 had no effect on the viability of A549 cells, it strongly suppressed DHA-induced autophagy and apoptosis as evidenced by a reduction in LC3-II and viability (Figures 3(a) and 3(b)). These results imply that autophagy, at least partially, contributes to DHA-induced apoptotic cell death.


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

Kim N, Jeong S, Jing K, Shin S, Kim S, Heo JY, Kweon GR, Park SK, Wu T, Park JI, Lim K - Biomed Res Int (2015)

DHA-induced autophagy is required for apoptotic cell death. The indicated cancer cell lines were treated with nontargeting control small interfering RNA (siNC) or siRNAs specific for autophagy-related Atg5 (a) and Atg7 (b). At 18 h after transfection, cells were incubated with the indicated doses of DHA for 24 h. Next, cells were harvested and subjected to western blot analysis with the following antibodies: Atg5, Atg7, LC3-II, and actin (upper panel). Cell viability was measured in an MTT assay (lower panel). ∗∗P < 0.01 and ∗∗∗P < 0.001. Data are representative of three independent experiments, all with similar results.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4538321&req=5

fig3: DHA-induced autophagy is required for apoptotic cell death. The indicated cancer cell lines were treated with nontargeting control small interfering RNA (siNC) or siRNAs specific for autophagy-related Atg5 (a) and Atg7 (b). At 18 h after transfection, cells were incubated with the indicated doses of DHA for 24 h. Next, cells were harvested and subjected to western blot analysis with the following antibodies: Atg5, Atg7, LC3-II, and actin (upper panel). Cell viability was measured in an MTT assay (lower panel). ∗∗P < 0.01 and ∗∗∗P < 0.001. Data are representative of three independent experiments, all with similar results.
Mentions: To unveil the relationship between DHA-autophagy and DHA-apoptotic cell death, we used siRNAs to knock down two essential autophagy gene products, Atg5 and Atg7. Although silencing of Atg5 and Atg7 had no effect on the viability of A549 cells, it strongly suppressed DHA-induced autophagy and apoptosis as evidenced by a reduction in LC3-II and viability (Figures 3(a) and 3(b)). These results imply that autophagy, at least partially, contributes to DHA-induced apoptotic cell death.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea ; Infection Signaling Network Research Center, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.

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.

No MeSH data available.


Related in: MedlinePlus