ATM/CHK/p53 Pathway Dependent Chemopreventive and Therapeutic Activity on Lung Cancer by Pterostilbene

PLoS One. 2016 Sep 9;11(9):e0162335. doi: 10.1371/journal.pone.0162335. eCollection 2016.


Among the many stilbenoids found in a variety of berries, resveratrol and pterostilbene are of particular interest given their potential for use in cancer therapeutics and prevention. We purified four stilbenoids from R. undulatum and found that pterostilbene inhibits cancer cell proliferation more efficiently than rhapontigenin, piceatannol and resveratrol. To investigate the underlying mechanism of this superior action of pterostilbene on cancer cells, we utilized a reverse-phase protein array followed by bioinformatic analysis and found that the ATM/CHK pathway is modified by pterostilbene in a lung cancer cell line. Given that ATM/CHK signaling requires p53 for its biological effects, we hypothesized that p53 is required for the anticancer effect of pterostilbene. To test this hypothesis, we used two molecularly defined precancerous human bronchial epithelial cell lines, HBECR and HBECR/p53i, with normal p53 and suppressed p53 expression, respectively, to represent premalignant states of squamous lung carcinogenesis. Pterostilbene inhibited the cell cycle more efficiently in HBECR cells compared to HBECR/p53i cells, suggesting that the presence of p53 is required for the action of pterostilbene. Pterostilbene also activated ATM and CHK1/2, which are upstream of p53, in both cell lines, though pterostilbene-induced senescence was dependent on the presence of p53. Finally, pterostilbene more effectively inhibited p53-dependent cell proliferation compared to the other three stilbenoids. These results strongly support the potential chemopreventive effect of pterostilbene on p53-positive cells during early carcinogenesis.

MeSH terms

  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Checkpoint Kinase 1 / metabolism
  • Checkpoint Kinase 2 / metabolism
  • Humans
  • Lung Neoplasms / drug therapy*
  • Proteome / drug effects
  • Respiratory Mucosa / drug effects
  • Resveratrol
  • Rheum / chemistry*
  • Signal Transduction / drug effects*
  • Stilbenes / therapeutic use*
  • Tumor Suppressor Protein p53 / metabolism


  • Antineoplastic Agents, Phytogenic
  • Proteome
  • Stilbenes
  • Tumor Suppressor Protein p53
  • rhapontigenin
  • pterostilbene
  • 3,3',4,5'-tetrahydroxystilbene
  • Checkpoint Kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • CHEK2 protein, human
  • Checkpoint Kinase 1
  • Resveratrol

Grant support

This work was supported by National Research Foundation (NRF) of Korea grant funded by the Korea government, Bio & Medical Technology Development Program, Basic Science Research Program and MSIP (NRF-2012M3A9B6055466, NRF-2015R1D1A1A01056594 and 2011-0030074, respectively). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.