Involvement of Akt/NF-κB Pathway in N6-isopentenyladenosine-induced Apoptosis in Human Breast Cancer Cells

Mol Carcinog. 2010 Oct;49(10):892-901. doi: 10.1002/mc.20666.

Abstract

N(6)-isopentenyladenosine (i6A) inhibits the tumor cell growth by inducing cell apoptosis in various cancer cell lines. However, little is known regarding the mechanisms by which the drug induces cell apoptosis. In this study, we further explored the molecular mechanisms of i6A as an anticancer agent on a human breast cancer cell line MDA MB 231. Treatment with i6A decreased the cell proliferation of MDA MB 231 cells in a dose-dependent manner by arresting the cells at G(0)/G(1) phase. This effect was strongly associated with concomitant decrease in the level of cyclin D1, cyclin E, cdk2, and increase of p21waf1 and p27kip. In addition i6A also induced apoptotic cell death by increasing the expression of Bax, and decreasing the levels of Bcl-2 and Bcl-xL, and subsequently triggered mitochondria apoptotic pathway (release of cytochrome c and activation of caspase-3). We observed that i6A suppressed the nuclear factor kappaB (NF-κB) pathway and inhibited the Akt activation. The results of this study indicate that i6A decreases cell proliferation and induces apoptotic cell death in human breast cancer cells, possibly by decreasing signal transduction through the Akt/NF-κB cell survival pathway.

MeSH terms

  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Caspase 3 / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Nucleus / pathology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase 2 / metabolism*
  • Cytochromes c / metabolism
  • Cytochromes c / pharmacology
  • Cytochromes c / therapeutic use
  • Female
  • Humans
  • Isopentenyladenosine / metabolism
  • Isopentenyladenosine / pharmacology*
  • Isopentenyladenosine / therapeutic use
  • NF-kappa B / metabolism*
  • NF-kappa B / pharmacology
  • NF-kappa B / therapeutic use
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects
  • bcl-2-Associated X Protein / metabolism
  • bcl-2-Associated X Protein / pharmacology

Substances

  • Antineoplastic Agents
  • NF-kappa B
  • bcl-2-Associated X Protein
  • Isopentenyladenosine
  • Cytochromes c
  • Proto-Oncogene Proteins c-akt
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Caspase 3