PPARγ ligands inhibit telomerase activity and hTERT expression through modulation of the Myc/Mad/Max network in colon cancer cells

Cristina Toaldo, Stefania Pizzimenti, Angelo Cerbone, Piergiorgio Pettazzoni, Elisa Menegatti, Berardi Daniela, Rosalba Minelli, Barbara Giglioni, Mario Umberto Dianzani, Carlo Ferretti, Giuseppina Barrera

Research output: Contribution to journalArticle

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Abstract

In human cells the length of telomeres depends on telomerase activity. This activity and the expression of the catalytic subunit of human telomerase reverse transcriptase (hTERT) is strongly up-regulated in most human cancers. hTERT expression is regulated by different transcription factors, such as c-Myc, Mad1 and Sp1. In this study, we demonstrated that 15d-PG J2 and rosiglitazone (an endogenous and synthetic peroxisome proliferators activated receptor γ (PPARγ) ligand, respectively) inhibited hTERT expression and telomerase activity in CaCo-2 colon cancer cells. Moreover, both ligands inhibited c-Myc protein expression and its E-box DNA binding activity. Additionally, Mad1 protein expression and its E-box DNA binding activity were strongly increased by 15d-PG J2 and, to a lesser extent, by rosiglitazone. Sp1 transcription factor expression and its GC-box DNA binding activity were not affected by both PPARγ ligands. Results obtained by transient transfection of CaCo-2 cells with pmaxFP-Green-PRL plasmid constructs containing the functional hTERT core promoter (including one E-box and five GC-boxes) and its E-box deleted sequences, cloned upstream of the green fluorescent protein reporter gene, demonstrated that 15d-PG J2, and with minor effectiveness, rosiglitazone, strongly reduced hTERT core promoter activity. E-boxes for Myc/Mad/Max binding showed a higher activity than GC-boxes for Sp1. By using GW9662, an antagonist of PPARγ, we demonstrated that the effects of 15d-PG J2 are completely PPARγ independent, whereas the effects of rosiglitazone on hTERT expression seem to be partially PPARγ independent. The regulation of hTERT expression by 15d-PG J2 and rosiglitazone, through the modulation of the Myc/Max/Mad1 network, may represent a new mechanism of action of these substances in inhibiting cell proliferation.

Original languageEnglish (US)
Pages (from-to)1347-1357
Number of pages11
JournalJournal of Cellular and Molecular Medicine
Volume14
Issue number6 A
DOIs
StatePublished - Jun 1 2010

Fingerprint

rosiglitazone
Peroxisome Proliferator-Activated Receptors
Telomerase
Colonic Neoplasms
Ligands
DNA
E-Box Elements
Proto-Oncogene Proteins c-myc
Sp1 Transcription Factor
Caco-2 Cells
Telomere
Green Fluorescent Proteins
human TERT protein
Reporter Genes
Transfection
Catalytic Domain
Plasmids
Transcription Factors
Cell Proliferation

Keywords

  • 15-deoxy-prostaglandin J2
  • CaCo-2 cells
  • GW9662
  • H-TERT
  • Myc/Mad/Max network
  • PPARγ ligands
  • Rosiglitazone
  • Sp1
  • Telomerase activity

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

Cite this

PPARγ ligands inhibit telomerase activity and hTERT expression through modulation of the Myc/Mad/Max network in colon cancer cells. / Toaldo, Cristina; Pizzimenti, Stefania; Cerbone, Angelo; Pettazzoni, Piergiorgio; Menegatti, Elisa; Daniela, Berardi; Minelli, Rosalba; Giglioni, Barbara; Dianzani, Mario Umberto; Ferretti, Carlo; Barrera, Giuseppina.

In: Journal of Cellular and Molecular Medicine, Vol. 14, No. 6 A, 01.06.2010, p. 1347-1357.

Research output: Contribution to journalArticle

Toaldo, C, Pizzimenti, S, Cerbone, A, Pettazzoni, P, Menegatti, E, Daniela, B, Minelli, R, Giglioni, B, Dianzani, MU, Ferretti, C & Barrera, G 2010, 'PPARγ ligands inhibit telomerase activity and hTERT expression through modulation of the Myc/Mad/Max network in colon cancer cells', Journal of Cellular and Molecular Medicine, vol. 14, no. 6 A, pp. 1347-1357. https://doi.org/10.1111/j.1582-4934.2009.00966.x
Toaldo, Cristina ; Pizzimenti, Stefania ; Cerbone, Angelo ; Pettazzoni, Piergiorgio ; Menegatti, Elisa ; Daniela, Berardi ; Minelli, Rosalba ; Giglioni, Barbara ; Dianzani, Mario Umberto ; Ferretti, Carlo ; Barrera, Giuseppina. / PPARγ ligands inhibit telomerase activity and hTERT expression through modulation of the Myc/Mad/Max network in colon cancer cells. In: Journal of Cellular and Molecular Medicine. 2010 ; Vol. 14, No. 6 A. pp. 1347-1357.
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