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Induction of Apoptosis in Pancreatic Cancer Cells by CDDO-Me Involves Repression of Telomerase through Epigenetic

Dorrah Deeb1, Chris Brigolin2, Xiaohua Gao1

  • 1Department of Surgery, Henry Ford Health System, Detroit, USA.

Journal of Carcinogenesis & Mutagenesis
|August 26, 2014
PubMed

Insights

Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) effectively targets pancreatic cancer by inhibiting telomerase. This synthetic triterpenoid induces apoptosis through epigenetic modifications, offering a novel therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Telomerase reactivation is crucial for cancer cell proliferation and survival.
  • Targeting telomerase offers a promising strategy for cancer therapy.
  • Pancreatic cancer remains a significant health challenge with limited effective treatments.

Purpose of the Study:

  • To investigate the effects of Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) on pancreatic cancer cells.
  • To elucidate the mechanisms by which CDDO-Me inhibits telomerase activity.
  • To explore the potential of CDDO-Me as a novel therapeutic agent for pancreatic cancer.

Main Methods:

  • Cell proliferation and apoptosis assays in pancreatic cancer cells treated with CDDO-Me.
  • Analysis of human telomerase reverse transcriptase (hTERT) mRNA, protein levels, and telomerase activity.
  • Investigation of transcription factor regulation (Sp1, c-Myc, NF-κB, CTCF, E2F-1, MAD1) of hTERT.
  • Assessment of DNA methyltransferases (DNMT1, DNMT3a) and hTERT promoter methylation.
  • Chromatin analysis of histone modifications (acetylation, methylation) at the hTERT promoter using chromatin immunoprecipitation.

Main Results:

  • CDDO-Me significantly inhibited pancreatic cancer cell proliferation and induced apoptosis at low concentrations.
  • CDDO-Me treatment led to decreased hTERT mRNA, hTERT protein, and telomerase activity.
  • CDDO-Me modulated key transcription factors regulating hTERT expression and inhibited DNA methyltransferases, leading to hTERT promoter hypomethylation.
  • Epigenetic modifications, including reduced histone acetylation and demethylation at the hTERT promoter, were observed.

Conclusions:

  • CDDO-Me effectively down-regulates telomerase in pancreatic cancer cells.
  • Epigenetic mechanisms, including modulation of transcription factors, DNA methylation, and histone modifications, are critical for CDDO-Me's anti-cancer effects.
  • CDDO-Me demonstrates potential as a novel therapeutic agent for pancreatic cancer by targeting telomerase through epigenetic regulation.
Keywords:
ApoptosisCDDO-MeEpigenetic controlTelomerasehTERT

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