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      Modulation of Telomerase Activity in Cancer Cells by Dietary Compounds: A Review

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          Abstract

          Telomerase is expressed in ~90% of human cancer cell lines and tumor specimens, whereas its enzymatic activity is not detectable in most human somatic cells, suggesting that telomerase represents a highly attractive target for selective cancer treatment. Accordingly, various classes of telomerase inhibitors have been screened and developed in recent years. We and other researchers have successfully found that some dietary compounds can modulate telomerase activity in cancer cells. Telomerase inhibitors derived from food are subdivided into two groups: one group directly blocks the enzymatic activity of telomerase (e.g., catechin and sulfoquinovosyldiacylglycerol), and the other downregulates the expression of human telomerase reverse transcriptase (hTERT), the catalytic subunit of human telomerase, via signal transduction pathways (e.g., retinoic acid and tocotrienol). In contrast, a few dietary components, including genistein and glycated lipid, induce cellular telomerase activity in several types of cancer cells, suggesting that they may be involved in tumor progression. This review summarizes the current knowledge about the effects of dietary factors on telomerase regulation in cancer cells and discusses their molecular mechanisms of action.

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          Systematic analysis of telomere length and somatic alterations in 31 cancer types

          Siyuan Zheng, Roel Verhaak and colleagues report an analysis of telomere lengths and somatic alterations in telomere-related pathways across 31 cancer types. Their study provides an overview of the molecular mechanisms driving TERT expression and activation of the ALT pathway, and identifies a subset of tumors with neither detectable TERT expression nor somatic alterations in ATRX or DAXX.
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            Telomere elongation in immortal human cells without detectable telomerase activity.

            Immortalization of human cells is often associated with reactivation of telomerase, a ribonucleoprotein enzyme that adds TTAGGG repeats onto telomeres and compensates for their shortening. We examined whether telomerase activation is necessary for immortalization. All normal human fibroblasts tested were negative for telomerase activity. Thirteen out of 13 DNA tumor virus-transformed cell cultures were also negative in the pre-crisis (i.e. non-immortalized) stage. Of 35 immortalized cell lines, 20 had telomerase activity as expected, but 15 had no detectable telomerase. The 15 telomerase-negative immortalized cell lines all had very long and heterogeneous telomeres of up to 50 kb. Hybrids between telomerase-negative and telomerase-positive cells senesced. Two senescent hybrids demonstrated telomerase activity, indicating that activation of telomerase is not sufficient for immortalization. Some hybrid clones subsequently recommenced proliferation and became immortalized either with or without telomerase activity. Those without telomerase activity also had very long and heterogeneous telomeres. Taken together, these data suggest that the presence of lengthened or stabilized telomeres is necessary for immortalization, and that this may be achieved either by the reactivation of telomerase or by a novel and as yet unidentified mechanism.
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              hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization.

              Telomerase, the ribonucleoprotein enzyme that elongates telomeres, is repressed in normal human somatic cells but is reactivated during tumor progression. We report the cloning of a human gene, hEST2, that shares significant sequence similarity with the telomerase catalytic subunit genes of lower eukaryotes. hEST2 is expressed at high levels in primary tumors, cancer cell lines, and telomerase-positive tissues but is undetectable in telomerase-negative cell lines and differentiated telomerase-negative tissues. Moreover, the message is up-regulated concomitant with the activation of telomerase during the immortalization of cultured cells and down-regulated during in vitro cellular differentiation. Taken together, these observations suggest that the induction of hEST2 mRNA expression is required for the telomerase activation that occurs during cellular immortalization and tumor progression.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                06 February 2018
                February 2018
                : 19
                : 2
                : 478
                Affiliations
                [1 ]Food & Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai 980-0845, Japan; nkgw@ 123456m.tohoku.ac.jp (K.N.); tyunkato@ 123456gmail.com (S.K.); junyai@ 123456tohoku.ac.jp (J.I.); fieldlily.716@ 123456gmail.com (Y.O.); soo.takasu@ 123456dc.tohoku.ac.jp (S.T.); nshimizu@ 123456dc.tohoku.ac.jp (N.S.); t-u.tak@ 123456dc.tohoku.ac.jp (T.T.)
                [2 ]Food and Biotechnology Innovation Project, New Industry Creation Hatchery Center (NICHe), Tohoku University, Sendai 980-8579, Japan; miyazawa@ 123456m.tohoku.ac.jp
                [3 ]Food and Health Science Research Unit, Graduate School of Agricultural Science, Tohoku University, Sendai 980-0845, Japan
                Author notes
                [* ]Correspondence: takahiro.eitsuka.a1@ 123456tohoku.ac.jp ; Tel.: +81-22-757-4418
                Article
                ijms-19-00478
                10.3390/ijms19020478
                5855700
                29415465
                4a5aa9ed-210c-4178-9ffa-9f5f0a733ec3
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 December 2017
                : 01 February 2018
                Categories
                Review

                Molecular biology
                telomerase,htert,cancer,dietary compound
                Molecular biology
                telomerase, htert, cancer, dietary compound

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