6-Shogaol, an Active Constituent of Dietary Ginger, Induces Autophagy by Inhibiting the AKT/mTOR Pathway in Human Non-Small Cell Lung Cancer A549 Cells

• Published in: Journal of agricultural and food chemistry Vol. 57; no. 20; pp. 9809 - 9816
• Main Authors: Hung, Jen-Yu, Hsu, Ya-Ling, Li, Chien-Te, Ko, Ying-Chin, Ni, Wen-Chiu, Huang, Ming-Shyan, Kuo, Po-Lin
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 28.10.2009
• Subjects: 6-shogaol; anticarcinogenic activity; Apoptosis; Apoptosis - drug effects; Aroma and flavouring agent industries; Autophagy; Autophagy - drug effects; biochemical pathways; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - physiopathology; Catechols; Catechols - pharmacology; cell death; Cell Line, Tumor; cell proliferation; chemistry; Down-Regulation; drug effects; drug therapy; Food industries; Fundamental and applied biological sciences. Psychology; gene expression; genetics; ginger; human cell lines; Humans; Intracellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; lung neoplasms; medicinal plants; medicinal properties; metabolism; Molecular Nutrition; pharmacology; physiopathology; Plant Extracts; Plant Extracts - pharmacology; protein kinases; protein phosphorylation; Protein Serine-Threonine Kinases; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; protein synthesis; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; signal transduction; Signal Transduction - drug effects; small interfering RNA; TOR Serine-Threonine Kinases; Zingiber officinale - chemistry; mTOR; human non-small cell lung cancer; AKT; autophagy; 6-Shogaol; Human; Lung; Spice; Ginger; Malignant tumor; Respiratory system; Cell; Constituent; Cancer
• ISSN: 0021-8561; 1520-5118; 1520-5118
• DOI: 10.1021/jf902315e

This study is the first study to investigate the anticancer effect of 6-shogaol in human non-small cell lung cancer A549 cells. 6-Shogaol inhibited cell proliferation by inducing autophagic cell death, but not, predominantly, apoptosis. Pretreatment of cells with 3-methyladenine (3-MA), an autophagy inhibitor, suppressed 6-shogaol mediated antiproliferation activity, suggesting that induction of autophagy by 6-shogaol is conducive to cell death. We also found that 6-shogaol inhibited survival signaling through the AKT/mTOR signaling pathway by blocking the activation of AKT and downstream targets, including the mammalian target of rapamycin (mTOR), forkhead transcription factors (FKHR) and glycogen synthase kinase-3β (GSK-3β). Phosphorylation of both of mTOR’s downstream targets, p70 ribosomal protein S6 kinase (p70S6 kinase) and 4E-BP1, was also diminished. Overexpression of AKT by AKT cDNA transfection decreased 6-shogaol mediated autophagic cell death, supporting inhibition of AKT beneficial to autophagy. Moreover, reduction of AKT expression by siRNA potentiated 6-shogaol’s effect, also supporting inhibition of AKT beneficial to autophagy. Taken together, these findings suggest that 6-shogaol may be a promising chemopreventive agent against human non-small cell lung cancer.