PPARgamma 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 [J Cell Mol Med] Journal article | | Title | PPARgamma ligands inhibit telomerase activity and hTERT expression through modulation of the Myc/Mad/Max network, in colon cancer cells. | | Author(s) | Toaldo C, Pizzimenti S, Cerbone A, Pettazzoni P, Menegatti E, Daniela B, Minelli R, Giglioni B, Dianzani MU, Ferretti C, Barrera G | | Institution | Section of General Pathology, Department of Medicine and Experimental Oncology, University of Turin, 10125 Turin, Italy. | | Source | J Cell Mol Med 2009 Nov 13. | | Abstract | Abstract In human cells the length of telomeres depends on telomerase activity. This activity and the expression of the catalytic subunit of telomerase (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 PPARgamma 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 PPARgamma 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 GFP 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 PPARgamma, we demonstrated that the effects of 15d-PG J2 are completely PPARgamma-independent, whereas the effects of rosiglitazone on hTERT expression seems to be partially PPARgamma-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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19912441 |
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