Growth inhibition and induction of apoptosis in mesothelioma cells by selenium and dependence on selenoprotein SEP15 genotype Journal Article

  

Authors:	Apostolou, S.; Klein, J. O.; Mitsuuchi, Y.; Shetler, J. N.; Poulikakos, P. I.; Jhanwar, S. C.; Kruger, W. D.; Testa, J. R.
Article Title:	Growth inhibition and induction of apoptosis in mesothelioma cells by selenium and dependence on selenoprotein SEP15 genotype
Abstract:	Malignant mesotheliomas (MMs) are aggressive tumors derived from mesothelial cells lining the lungs, pericardium and peritoneum, and are often associated with occupational asbestos exposure. Suppression subtractive hybridization was used to identify genes differentially expressed in MM cells compared to normal mesothelial cells. A gene, SEP15, encoding a 15-kDa selenium-containing protein was isolated using this approach and was subsequently shown to be downregulated in ∼60% of MM cell lines and tumor specimens. A SEP15 polymorphic variant, 1125A, resides in the SECIS recognition element in the 3′-UTR and may influence the efficiency of Sec incorporation into the protein during translation. Since previous studies have implicated a potential role of the trace element selenium as a chemopreventive agent in animal models and in several types of human cancer, we investigated the effect of selenium on MM cells and its dependence on SEP15 genotype. Selenium was shown to inhibit cell growth and induce apoptosis in a dose-dependent manner in MM cells but had minimal effect on normal mesothelial cells. However, MM cells with downregulated SEP15 or the 1125A variant were somewhat less responsive to the growth inhibitory and apoptotic effects of selenium than MM cells expressing wild-type protein. RNAi-based knockdown studies demonstrated that SEP15 inhibition makes sensitive MM cells more resistant to selenium. These data imply that selenium may be useful as a chemopreventive agent in individuals at high risk of MM due to asbestos exposure, although those with the 1125A polymorphism may be less responsive to the protective benefits of dietary selenium supplementation.
Keywords:	human cell; genetics; dose response; proteins; cell division; chemoprophylaxis; apoptosis; gene expression; cell growth; cell line; protein; small interfering rna; down-regulation; rna, small interfering; genetic variability; genotype; gene frequency; drug effect; pathology; tumor cells, cultured; transfection; diet supplementation; animalia; genetic transfection; cell culture; gene identification; data analysis; mesothelioma; down regulation; selenium; heterozygosity loss; loss of heterozygosity; molecular weight; genetic code; rna induced silencing complex; mesothelium cell; dna polymorphism; growth inhibition; chemoprevention; suppression subtractive hybridization; variation (genetics); selenoprotein; humans; human; priority journal; article; sep15 genotype; sep15 protein, human; selenoproteins
Journal Title:	Oncogene
Volume:	23
Issue:	29
ISSN:	0950-9232
Publisher:	Nature Publishing Group
Date Published:	2004-04-26
Start Page:	5032
End Page:	5040
Language:	English
DOI:	10.1038/sj.onc.1207683
PROVIDER:	scopus
PUBMED:	15107826
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-3042743368&partnerID=40&md5=d5d820cc3264bedf34c671df37c5b1a0
Notes:	Oncogene -- Cited By (since 1996):45 -- Export Date: 16 June 2014 -- CODEN: ONCNE -- Source: Scopus

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