Delta-tocotrienol suppresses Notch-1 pathway by upregulating miR-34a in nonsmall cell lung cancer cells

Int J Cancer. 2012 Dec 1;131(11):2668-77. doi: 10.1002/ijc.27549. Epub 2012 Jun 26.


MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating various cellular functions by transcriptional silencing. miRNAs can function as either oncogenes or tumor suppressors (oncomirs), depending on cancer types. In our study, using miRNA microarray, we observed that downregulation of the Notch-1 pathway, by delta-tocotrienol, correlated with upregulation of miR-34a, in nonsmall cell lung cancer cells (NSCLC). Moreover, re-expression of miR-34a by transfection in NSCLC cells resulted in inhibition of cell growth and invasiveness, induction of apoptosis and enhanced p53 activity. Furthermore, cellular mechanism studies revealed that induction of miR-34a decreased the expression of Notch-1 and its downstream targets including Hes-1, Cyclin D1, Survivin and Bcl-2. Our findings suggest that delta-tocotrienol is a nontoxic activator of mir-34a which can inhibit NSCLC cell proliferation, induce apoptosis and inhibit invasion, and thus offering a potential starting point for the design of novel anticancer agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin D1 / genetics
  • Down-Regulation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Homeodomain Proteins / genetics
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics*
  • Neoplasm Invasiveness
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Signal Transduction / drug effects*
  • Survivin
  • Transcription Factor HES-1
  • Transfection / methods
  • Tumor Suppressor Protein p53 / genetics
  • Up-Regulation / drug effects
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology


  • BIRC5 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • Inhibitor of Apoptosis Proteins
  • MIRN34 microRNA, human
  • MicroRNAs
  • NOTCH1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Receptor, Notch1
  • Survivin
  • TP53 protein, human
  • Transcription Factor HES-1
  • Tumor Suppressor Protein p53
  • Cyclin D1
  • Vitamin E
  • HES1 protein, human
  • tocotrienol, delta