Ibandronate increases the expression of the pro-apoptotic gene FAS by epigenetic mechanisms in tumor cells

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R Thaler1, S Spitzer, H Karlic

  • 1Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria.

Biochemical Pharmacology
|October 30, 2012
PubMed

Insights

Aminobisphosphonates like ibandronate induce cancer cell death by inhibiting small GTPase activity. This epigenetic mechanism involves DNA demethylation and FAS gene upregulation, leading to apoptosis in neoplastic cells.

Area of Science:

  • Biochemistry
  • Epigenetics
  • Cancer Biology

Background:

  • Aminobisphosphonates, such as ibandronate, exhibit anticancer effects through poorly understood mechanisms.
  • These drugs inhibit the posttranslational isoprenylation of small GTPases, crucial for cell signaling.
  • In cancer cells, activated RAS-GTPase downregulates the pro-apoptotic FAS gene via DNA methylation mediated by DNMT1.

Purpose of the Study:

  • To investigate the anticancer mechanism of ibandronate in neoplastic and non-neoplastic cells.
  • To determine the effect of ibandronate on cell proliferation, apoptosis, and gene expression.
  • To elucidate the role of epigenetic modifications, specifically DNA methylation and demethylation, in ibandronate's action.

Main Methods:

  • Treatment of human osteosarcoma (U-2) and mouse breast cancer (CCL-51) cells, alongside non-neoplastic osteoblastic (MC3T3-E1) cells, with ibandronate.
  • Assessment of cell proliferation rates across all cell lines.
  • Analysis of caspase activation, FAS expression, DNMT1 levels, and DNA methylation status following ibandronate treatment.
  • Investigation of the rescue effect of geranylgeranyl-pyrophosphate and farnesylpyrophosphate on DNMT1 activity.

Main Results:

  • Ibandronate attenuated proliferation in all tested cell lines.
  • Neoplastic cells exhibited increased caspase activity, indicating apoptosis.
  • FAS expression was upregulated in cancer cells due to DNA demethylation, linked to DNMT1 downregulation.
  • DNMT1 downregulation was reversible by re-isoprenylation, while non-neoplastic cells showed no changes in FAS or DNMT1 expression.

Conclusions:

  • Bisphosphonates induce apoptosis in neoplastic cells by modulating small GTPase activity, leading to DNA-CpG demethylation and FAS expression stimulation.
  • This epigenetic mechanism explains the anti-neoplastic activity of farnesyl-transferase inhibition.
  • The findings provide insight into the clinical efficacy of drugs targeting this pathway.

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