Genome-wide inhibitory impact of the AMPK activator metformin on [kinesins, tubulins, histones, auroras and polo-like kinases] M-phase cell cycle genes in human breast cancer cells

Cell Cycle. 2009 May 15;8(10):1633-6. doi: 10.4161/cc.8.10.8406. Epub 2009 May 13.

Abstract

Prompted by the ever-growing scientific rationale for examining the antidiabetic drug metformin as a potential antitumor agent in breast cancer disease, we recently tested the hypothesis that the assessment of metformin-induced global changes in gene expression-as identified using 44 K (double density) Agilent's whole human genome arrays-could reveal gene-expression signatures that would allow proper selection of breast cancer patients who should be considered for metformin-based clinical trials. Using Database for Annotation, Visualization and Integrated Discovery bioinformatics (DAVID) resources we herein reveal that, at doses that lead to activation of the AMP-activated protein kinase (AMPK), metformin not only downregulates genes coding for ribosomal proteins (i.e., protein and macromolecule biosynthesis) but unexpectedly suppresses numerous mitosis-related gene families including kinesins, tubulins, histones, auroras and polo-like kinases. This is, to our knowledge, the first genome-scale evidence of a mitotic core component in the transcriptional response of human breast cancer cells to metformin. These findings further support a tight relationship between the activation status of AMPK and the chromosomal and cytoskeletal checkpoints of cell mitosis at the transcriptional level.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Aurora Kinases
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Division / genetics*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / genetics*
  • Genome, Human / genetics*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Kinesin / genetics
  • Kinesin / metabolism
  • Metformin / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Tubulin / genetics
  • Tubulin / metabolism

Substances

  • Cell Cycle Proteins
  • Histones
  • Tubulin
  • Metformin
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Kinesin