Inhibition of telomerase activity by oleanane triterpenoid CDDO-Me in pancreatic cancer cells is ROS-dependent

Dorrah Deeb, Xiaohua Gao, Yongbo Liu, Nadimpalli R.S. Varma, Ali Syed Arbab, Subhash C. Gautam

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) is a synthetic derivative of oleanolic acid, a triterpene, with apoptosis-inducing activity in a wide range of cancer cells. Induction of apoptosis by CDDO-Me is associated with the generation of reactive oxygen species (ROS) and inhibition of telomerase activity. In the present study, we investigated the role of ROS in inhibition of telomerase by CDDO-me. Treatment of MiaPaCa-2 and Panc-1 pancreatic cancer cell lines with CDDO-Me induced the production of hydrogen peroxide and superoxide anions and inhibited the telomerase activity. Pretreatment of cells with N-acetylcycsteine, a general purpose antioxidant or overexpression of glutathione peroxidase (GPx) or superoxide dismutase-1 (SOD-1) blocked the telomerase inhibitory activity of CDDO-Me. Furthermore, blocking ROS generation also prevented the inhibition of hTERT gene expression, hTERT protein production and expression of a number of hTERT-regulatory proteins by CDDO-Me (e.g., c-Myc, Sp1, NF-κB and p-Akt). Data also showed that Akt plays an important role in the activation of telomerase activity. Together, these data suggest that inhibition of telomerase activity by CDDO-Me is mediated through a ROS-dependent mechanism; however, more work is needed to fully understand the role of ROS in down-regulation of hTERT gene and hTERT-regulatory proteins by CDDO-Me.

Original languageEnglish (US)
Pages (from-to)3250-3265
Number of pages16
JournalMolecules
Volume18
Issue number3
DOIs
StatePublished - Mar 1 2013
Externally publishedYes

Fingerprint

Telomerase
Pancreatic Neoplasms
Reactive Oxygen Species
cancer
Cells
oxygen
inorganic peroxides
apoptosis
proteins
Apoptosis
Oleanolic Acid
Triterpenes
Proteins
glutathione
gene expression
antioxidants
Regulator Genes
Glutathione Peroxidase
hydrogen peroxide
cultured cells

Keywords

  • CDDO-Me
  • HTERT
  • Pancreatic cancer
  • ROS
  • Telomerase activity

ASJC Scopus subject areas

  • Medicine(all)
  • Organic Chemistry

Cite this

Inhibition of telomerase activity by oleanane triterpenoid CDDO-Me in pancreatic cancer cells is ROS-dependent. / Deeb, Dorrah; Gao, Xiaohua; Liu, Yongbo; Varma, Nadimpalli R.S.; Arbab, Ali Syed; Gautam, Subhash C.

In: Molecules, Vol. 18, No. 3, 01.03.2013, p. 3250-3265.

Research output: Contribution to journalArticle

Deeb, Dorrah ; Gao, Xiaohua ; Liu, Yongbo ; Varma, Nadimpalli R.S. ; Arbab, Ali Syed ; Gautam, Subhash C. / Inhibition of telomerase activity by oleanane triterpenoid CDDO-Me in pancreatic cancer cells is ROS-dependent. In: Molecules. 2013 ; Vol. 18, No. 3. pp. 3250-3265.
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AB - Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) is a synthetic derivative of oleanolic acid, a triterpene, with apoptosis-inducing activity in a wide range of cancer cells. Induction of apoptosis by CDDO-Me is associated with the generation of reactive oxygen species (ROS) and inhibition of telomerase activity. In the present study, we investigated the role of ROS in inhibition of telomerase by CDDO-me. Treatment of MiaPaCa-2 and Panc-1 pancreatic cancer cell lines with CDDO-Me induced the production of hydrogen peroxide and superoxide anions and inhibited the telomerase activity. Pretreatment of cells with N-acetylcycsteine, a general purpose antioxidant or overexpression of glutathione peroxidase (GPx) or superoxide dismutase-1 (SOD-1) blocked the telomerase inhibitory activity of CDDO-Me. Furthermore, blocking ROS generation also prevented the inhibition of hTERT gene expression, hTERT protein production and expression of a number of hTERT-regulatory proteins by CDDO-Me (e.g., c-Myc, Sp1, NF-κB and p-Akt). Data also showed that Akt plays an important role in the activation of telomerase activity. Together, these data suggest that inhibition of telomerase activity by CDDO-Me is mediated through a ROS-dependent mechanism; however, more work is needed to fully understand the role of ROS in down-regulation of hTERT gene and hTERT-regulatory proteins by CDDO-Me.

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