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http://dx.doi.org/10.7314/APJCP.2016.17.3.957

Effects of 5-Aza-2'-Deoxycytidine, Bromodeoxyuridine, Interferons and Hydrogen Peroxide on Cellular Senescence in Cholangiocarcinoma Cells  

Moolmuang, Benchamart (Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute)
Singhirunnusorn, Pattama (Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute)
Ruchirawat, Mathuros (Laboratory of Environmental Toxicology, Chulabhorn Research Institute)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.17, no.3, 2016 , pp. 957-963 More about this Journal
Abstract
Cellular senescence, a barrier to tumorigenesis, controls aberrant proliferation of cells. We here aimed to investigate cellular senescence in immortalized cholangiocyte and cholangiocarcinoma cell lines using five different inducing agents: 5-aza-2'deoxycytidine, bromodeoxyuridine, interferons ($IFN{\beta}$ and $IFN{\gamma}$), and hydrogen peroxide. We analyzed senescence characteristics, colony formation ability, expression of genes involved in cell cycling and interferon signaling pathways, and protein levels. Treatment with all five agents decreased cell proliferation and induced cellular senescence in immortalized cholangiocyte and cholangiocarcinoma cell lines with different degrees of growth-inhibitory effects depending on cell type and origin. Bromodeoxyuridine gave the strongest stimulus to inhibit growth and induce senescence in most cell lines tested. Expression of p21 and interferon related genes was upregulated in most conditions. The fact that bromodeoxyuridine had the strongest effects on growth inhibition and senescence induction implies that senescence in cholangiocarcinoma cells is likely controlled by DNA damage response pathways relating to the p53/p21 signaling. In addition, interferon signaling pathways may partly regulate this mechanism in cholangiocarcinoma cells.
Keywords
Cholangiocarcinoma cells; cellular senescence; 5-aza-2'-deoxycytidine; bromodeoxyuridine; interferons;
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1 Braumuller H, Wieder T, Brenner E, et al (2013). T-helper-1-cell cytokines drive cancer into senescence. Nature, 494, 361-5.   DOI
2 Chen Q, Ames BN (1994). Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. Proc Natl Acad Sci USA, 91, 4130-4.   DOI
3 Chiantore MV, Vannucchi S, Accardi R, et al (2012). Interferon-beta induces cellular senescence in cutaneous human papilloma virus-transformed human keratinocytes by affecting p53 transactivating activity. PLoS One, 7, 36909.   DOI
4 Clarke CJ, Hii LL, Bolden JE, et al (2010). Inducible activation of IFI 16 results in suppression of telomerase activity, growth suppression and induction of cellular senescence. J Cell Biochem, 109, 103-12.
5 Collado M, Gil J, Efeyan A, et al (2005). Tumour biology: senescence in premalignant tumours. Nature, 436, 642.   DOI
6 Coppe JP, Desprez PY, Krtolica A, et al (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol, 5, 99-118.   DOI
7 Di GH, Liu Y, Lu Y, et al (2014). IL-6 secreted from senescent mesenchymal stem cells promotes proliferation and migration of breast cancer cells. PLoS One, 9, 113572.   DOI
8 Dimri GP, Lee X, Basile G, et al (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A, 92, 9363-7.   DOI
9 Fitzgerald AL, Osman AA, Xie TX, et al (2015). Reactive oxygen species and p21Waf1/Cip1 are both essential for p53-mediated senescence of head and neck cancer cells. Cell Death Dis, 6, 1678.   DOI
10 Fridman AL, Tang L, Kulaeva OI, et al (2006). Expression profiling identifies three pathways altered in cellular immortalization: interferon, cell cycle, and cytoskeleton. J Gerontol A Biol Sci Med Sci, 61, 879-89.   DOI
11 Haaf T (1995). The effects of 5-azacytidine and 5-azadeoxycytidine on chromosome structure and function: implications for methylation-associated cellular processes. Pharmacol Ther, 65, 19-46.   DOI
12 Halliwell B (2007). Oxidative stress and cancer: have we moved forward? Biochem J, 401, 1-11.   DOI
13 Hubackova S, Kucerova A, Michlits G, et al (2015). IFNgamma induces oxidative stress, DNA damage and tumor cell senescence via TGFbeta/SMAD signaling-dependent induction of Nox4 and suppression of ANT2. Oncogene, (in Press)
14 Khan SA, Toledano MB, Taylor-Robinson SD (2008). Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB (Oxford), 10, 77-82.   DOI
15 Kim KS, Kang KW, Seu YB, et al (2009). Interferon-gamma induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells. Mech Ageing Dev, 130, 179-88.   DOI
16 Kubo S, Kinoshita H, Hirohashi K, et al (1995). Hepatolithiasis associated with cholangiocarcinoma. World J Surg, 19, 637-41.   DOI
17 Kuilman T, Michaloglou C, Vredeveld LC, et al (2008). Oncogene-induced senescence relayed by an interleukindependent inflammatory network. Cell, 133, 1019-31.   DOI
18 Michishita E, Nakabayashi K, Suzuki T, et al (1999). 5-Bromodeoxyuridine induces senescence-like phenomena in mammalian cells regardless of cell type or species. J Biochem, 126, 1052-9.   DOI
19 Kulaeva OI, Draghici S, Tang L, et al (2003). Epigenetic silencing of multiple interferon pathway genes after cellular immortalization. Oncogene, 22, 4118-27.   DOI
20 Lazaridis KN, Gores GJ (2005). Cholangiocarcinoma. Gastroenterol, 128, 1655-67.   DOI
21 Moiseeva O, Mallette FA, Mukhopadhyay UK, et al (2006). DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation. Mol Biol Cell, 17, 1583-92.   DOI
22 Munoz-Espin D, Serrano M (2014). Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol, 15, 482-96.   DOI
23 Novakova Z, Hubackova S, Kosar M, et al (2010). Cytokine expression and signaling in drug-induced cellular senescence. Oncogene, 29, 273-84.   DOI
24 Parkin DM, Ohshima H, Srivatanakul P, et al (1993). Cholangiocarcinoma: epidemiology, mechanisms of carcinogenesis and prevention. Cancer Epidemiol Biomarkers Prev, 2, 537-44.
25 Rountree MR, Bachman KE, Herman JG, et al (2001). DNA methylation, chromatin inheritance, and cancer. Oncogene, 20, 3156-65.   DOI
26 Sasaki M, Ikeda H, Sato Y, et al (2008). Proinflammatory cytokine-induced cellular senescence of biliary epithelial cells is mediated via oxidative stress and activation of ATM pathway: a culture study. Free Radic Res, 42, 625-32.   DOI
27 Sirica AE (2005). Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy. Hepatol, 41, 5-15.   DOI
28 Suzuki T, Minagawa S, Michishita E, et al (2001). Induction of senescence-associated genes by 5-bromodeoxyuridine in HeLa cells. Exp Gerontol, 36, 465-74.   DOI
29 Sripa B, Kaewkes S, Sithithaworn P, et al (2007). Liver fluke induces cholangiocarcinoma. PLoS Med, 4, 201.   DOI
30 Struikmans H, Rutgers DH, Jansen GH, et al (1997). S-phase fraction, 5-bromo-2'-deoxy-uridine labelling index, duration of S-phase, potential doubling time, and DNA index in benign and malignant brain tumors. Radiat Oncol Investig, 5, 170-9.   DOI
31 Vatanasapt V, Uttaravichien T, Mairiang EO, et al (1990). Cholangiocarcinoma in north-east Thailand. Lancet, 335, 116-7.
32 Vogt M, Haggblom C, Yeargin J, et al (1998). Independent induction of senescence by p16INK4a and p21CIP1 in spontaneously immortalized human fibroblasts. Cell Growth Differ, 9, 139-46.
33 Wehbe H, Henson R, Meng F, et al (2006). Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res, 66, 10517-24.   DOI
34 Xin H, Pereira-Smith OM, Choubey D (2004). Role of IFI 16 in cellular senescence of human fibroblasts. Oncogene, 23, 6209-17.   DOI
35 Yoshizaki K, Fujiki T, Tsunematsu T, et al (2009). Pro-senescent effect of hydrogen peroxide on cancer cells and its possible application to tumor suppression. Biosci Biotechnol Biochem, 73, 311-5.   DOI
36 Yu Q, Katlinskaya YV, Carbone CJ, et al (2015). DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function. Cell Rep, 11, 785-97.   DOI