alexa Induction of Apoptosis in Pancreatic Cancer Cells by CD
ISSN: 2157-2518

Journal of Carcinogenesis & Mutagenesis
Open Access

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Research Article

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

Dorrah Deeb1, Chris Brigolin2, Xiaohua Gao1, Yongbo Liu1, Kirit R. Pindolia2 and Subhash C. Gautam1*
1Department of Surgery, Henry Ford Health System, Detroit, USA
2Department of Medical Genetics, Henry Ford Health System, Detroit, USA
Corresponding Author : Dr. Subhash C. Gautam, Ph.D
Surgical Research - 4D, Henry Ford Health System
One Ford Place, Detroit, MI 48202, USA
Tel: (313) 874-6998
Fax: (313) 874-3770
E-mail: [email protected]
Received March 06, 2014; Accepted May 27, 2014; Published May 31, 2014
Citation: Deeb D, Brigolin C, Gao X, Liu Y, Pindolia KR, et al. (2014) Induction of Apoptosis in Pancreatic Cancer Cells by CDDO-Me Involves Repression of Telomerase through Epigenetic Pathways. J Carcinog & Mutagen 5:177. doi: 10.4172/2157-2518.1000177
Copyright: © 2014 Deeb D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 

Abstract

Reactivation of telomerase in cancers provides an attractive target for developing novel agents to selectively destroy tumor cells. Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me), a synthetic oleanane triterpenoid, inhibited cell proliferation and induced apoptosis in pancreatic cancer cells at very low concentrations. The antiproliferative and apoptosis-inducing effects of CDDO-Me were associated with the inhibition of human telomerase reverse transcriptase (hTERT) mRNA, hTERT protein and reduction in hTERT telomerase activity. CDDO-Me inhibited multiple transcription factors that regulate hTERT expression positively (Sp1, c-Myc and NF-κB) and negatively (CTCF, E2F-1 and MAD1). CDDO-Me inhibited protein levels of DNA methyl transferases DNMT1 and DNMT3a, which also resulted in hypomethylation of hTERT promoter. In addition, transcriptionally active chromatin markers, such as acetylated histone H3 (Lys 9), acetylated histone H4, di-methyl H3 (Lys 4) and tri-methyl H3 (Lys 9) were all reduced in pancreatic cancer cells treated with CDDO-Me. Chromatin immunoprecipitation analysis showed decreased histone deacetylation and histone demethylation at hTERT promoter. Collectively, these results indicate that down-regulation of telomerase through epigenetic mechanisms plays a critical role in induction of apoptosis in pancreatic cancer cells by CDDO-Me

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