Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of cellular and molecular medicine, 2010-06, Vol.14 (6a), p.1347-1357

Ort / Verlag

Oxford, UK: Blackwell Publishing Ltd

Erscheinungsjahr

2010

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.