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

J Agric Food Chem. 2009 Oct 28;57(20):9809-16. doi: 10.1021/jf902315e.

Abstract

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-3beta (GSK-3beta). 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Autophagy / drug effects*
  • 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 / pharmacology*
  • Cell Line, Tumor
  • Down-Regulation
  • Ginger / chemistry*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Plant Extracts / pharmacology*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases

Substances

  • Catechols
  • Intracellular Signaling Peptides and Proteins
  • Plant Extracts
  • shogaol
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt