Advanced SearchSearch Tips
Effects of 5-Aza-2`-Deoxycytidine, Bromodeoxyuridine, Interferons and Hydrogen Peroxide on Cellular Senescence in Cholangiocarcinoma Cells
facebook(new window)  Pirnt(new window) E-mail(new window) Excel Download
 Title & Authors
Effects of 5-Aza-2`-Deoxycytidine, Bromodeoxyuridine, Interferons and Hydrogen Peroxide on Cellular Senescence in Cholangiocarcinoma Cells
Moolmuang, Benchamart; Singhirunnusorn, Pattama; Ruchirawat, Mathuros;
  PDF(new window)
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 ( and ), 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.
Cholangiocarcinoma cells;cellular senescence;5-aza-2`-deoxycytidine;bromodeoxyuridine;interferons;
 Cited by
Braumuller H, Wieder T, Brenner E, et al (2013). T-helper-1-cell cytokines drive cancer into senescence. Nature, 494, 361-5. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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.

Collado M, Gil J, Efeyan A, et al (2005). Tumour biology: senescence in premalignant tumours. Nature, 436, 642. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

Halliwell B (2007). Oxidative stress and cancer: have we moved forward? Biochem J, 401, 1-11. crossref(new window)

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)

Khan SA, Toledano MB, Taylor-Robinson SD (2008). Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB (Oxford), 10, 77-82. crossref(new window)

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. crossref(new window)

Kubo S, Kinoshita H, Hirohashi K, et al (1995). Hepatolithiasis associated with cholangiocarcinoma. World J Surg, 19, 637-41. crossref(new window)

Kuilman T, Michaloglou C, Vredeveld LC, et al (2008). Oncogene-induced senescence relayed by an interleukindependent inflammatory network. Cell, 133, 1019-31. crossref(new window)

Kulaeva OI, Draghici S, Tang L, et al (2003). Epigenetic silencing of multiple interferon pathway genes after cellular immortalization. Oncogene, 22, 4118-27. crossref(new window)

Lazaridis KN, Gores GJ (2005). Cholangiocarcinoma. Gastroenterol, 128, 1655-67. crossref(new window)

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. crossref(new window)

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. crossref(new window)

Munoz-Espin D, Serrano M (2014). Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol, 15, 482-96. crossref(new window)

Novakova Z, Hubackova S, Kosar M, et al (2010). Cytokine expression and signaling in drug-induced cellular senescence. Oncogene, 29, 273-84. crossref(new window)

Parkin DM, Ohshima H, Srivatanakul P, et al (1993). Cholangiocarcinoma: epidemiology, mechanisms of carcinogenesis and prevention. Cancer Epidemiol Biomarkers Prev, 2, 537-44.

Rountree MR, Bachman KE, Herman JG, et al (2001). DNA methylation, chromatin inheritance, and cancer. Oncogene, 20, 3156-65. crossref(new window)

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. crossref(new window)

Sirica AE (2005). Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy. Hepatol, 41, 5-15. crossref(new window)

Sripa B, Kaewkes S, Sithithaworn P, et al (2007). Liver fluke induces cholangiocarcinoma. PLoS Med, 4, 201. crossref(new window)

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. crossref(new window)

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. crossref(new window)

Vatanasapt V, Uttaravichien T, Mairiang EO, et al (1990). Cholangiocarcinoma in north-east Thailand. Lancet, 335, 116-7.

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.

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. crossref(new window)

Xin H, Pereira-Smith OM, Choubey D (2004). Role of IFI 16 in cellular senescence of human fibroblasts. Oncogene, 23, 6209-17. crossref(new window)

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. crossref(new window)

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. crossref(new window)