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Tumor Biology
Published in: Tumor Biology 5/2011

Open Access 01-10-2011 | Research Article

Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells

Authors: Magdalena Dabrowska, Marek Skoneczny, Wojciech Rode

Published in: Tumor Biology | Issue 5/2011

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Abstract

Cellular functions accompanying establishment of premature senescence in methotrexate-treated human colon cancer C85 cells are deciphered in the present study from validated competitive expression microarray data, analyzed with the use of Ingenuity Pathways Analysis (IPA) software. The nitrosative/oxidative stress, inferred from upregulated expression of inducible nitric oxide synthase (iNOS) and mitochondrial dysfunction-associated genes, including monoamine oxidases MAOA and MAOB, β-amyloid precursor protein (APP) and presenilin 1 (PSEN1), is identified as the main determinant of signaling pathways operating during senescence establishment. Activation of p53-signaling pathway is found associated with both apoptotic and autophagic components contributing to this process. Activation of nuclear factor κB (NF-κB), resulting from interferon γ (IFNγ), integrin, interleukin 1β (IL-1β), IL-4, IL-13, IL-22, Toll-like receptors (TLRs) 1, 2 and 3, growth factors and tumor necrosis factor (TNF) superfamily members signaling, is found to underpin inflammatory properties of senescent C85 cells. Upregulation of p21-activated kinases (PAK2 and PAK6), several Rho molecules and myosin regulatory light chains MYL12A and MYL12B, indicates acquisition of motility by those cells. Mitogen-activated protein kinase p38 MAPK β, extracellular signal-regulated kinases ERK2 and ERK5, protein kinase B AKT1, as well as calcium, are identified as factors coordinating signaling pathways in senescent C85 cells.
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Literature
1.
2.
d’Adda di Fagagna F. Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008;8:512–22.PubMedCrossRef
3.
Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8:729–40.PubMedCrossRef
4.
Gewirtz DA, Holt SE, Elmore LW. Accelerated senescence: an emerging role in tumor cell response to chemotherapy and radiation. Biochem Pharmacol. 2008;76:947–57.PubMedCrossRef
5.
Collado M, Serrano M. Senescence in tumours: evidence from mice and humans. Nat Rev Cancer. 2010;10:51–7.PubMedCrossRef
6.
Gewirtz DA. Autophagy, senescence and tumor dormancy in cancer therapy. Autophagy. 2009;5:1232–4.PubMedCrossRef
7.
Dabrowska M, Hendrikx PJ, Skierski J, Malinowska M, Bertino JR, Rode W. EGFP fluorescence as an indicator of cancer cells response to methotrexate. Eur J Pharmacol. 2007;555:93–9.PubMedCrossRef
8.
Dabrowska M, Mosieniak G, Skierski J, Sikora E, Rode W. Methotrexate-induced senescence in human adenocarcinoma cells is accompanied by induction of p21waf1/cip1 expression and lack of polyploidy. Cancer Lett. 2009;284:95–101.PubMedCrossRef
9.
Dabrowska M, Skoneczny M, Mosieniak G, Sikora E, Rode W. Expression of cell cycle checkpoints regulatory genes during methotrexate-induced senescence in human adenocarcinoma cells. Pteridines. 2009;20:143–7.
10.
Copeland NG, Jenkins NA. Deciphering the genetic landscape of cancer-from genes to pathways. Trends Genet. 2009;25:455–62.PubMedCrossRef
11.
Swanton C, Caldas C. Molecular classification of solid tumors: towards pathway-driven therapeutics. Br J Cancer. 2009;100:1517–22.PubMedCrossRef
12.
Longo GSA, Izzo J, Gorlick JR, Banerjee D, Jhanwar SC, Bertino JR. Characterization and drug sensitivity of four newly established colon adenocarcinoma cell lines to antifolate inhibitors of thymidylate synthase. Oncol Res. 2000;12:309–14.
13.
Zelcer S, Kellick M, Wexler LH, Gorlick R, Meyers PA. The Memorial Sloan Kettering Cancer Center experience with outpatient administration of high dose methotrexate with leucovorin rescue. Pediatr Blood Cancer. 2008;50:1176–80.PubMedCrossRef
14.
Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein A. A model for p53-induced apoptosis. Nature. 1997;389:300–5.PubMedCrossRef
15.
16.
Kumar MJ, Nicholls DG, Andersen JK. Oxidative α-ketoglutarate dehydrogenase inhibition via subtle elevations in monoamine oxidase B levels results in loss of spare respiratory capacity. J Biol Chem. 2003;278:46432–9.PubMedCrossRef
17.
Manoli I, Le H, Alesci S, McFann KK, Su YA, Kino T, et al. Monoamine oxidase-A is a major target gene for glucocorticoids in human skeletal muscle cells. FASEB J. 2005;19:1359–61.PubMed
18.
Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43:109–42.PubMed
19.
Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S, Peter ME. Apoptosis signaling by death receptors. Eur J Biochem. 1998;254:439–59.PubMedCrossRef
20.
Mruk DD, Cheng CY. Sertoli–Sertoli and Sertoli–germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis. Endocr Rev. 2004;25:747–806.PubMedCrossRef
21.
Dasari A, Bartholomew JN, Volonte D, Galbiati F. Oxidative stress induces premature senescence by stimulating caveolin-1 gene transcription through p38 mitogen-activated protein kinase/Sp1-mediated activation of two GC-rich promoter elements. Cancer Res. 2006;66:10805–14.PubMedCrossRef
22.
Khan EM, Heidinger JM, Levy M, Lisanti MP, Ravid T, Goldkorn T. Epidermal growth factor receptor exposed to oxidative stress undergoes src- and caveolin-1-dependent perinuclear trafficking. J Biol Chem. 2006;281:14486–93.PubMedCrossRef
23.
Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat Cell Biol. 2010;12:747–57.PubMedCrossRef
24.
Zhang H. Molecular signaling and genetic pathways of senescence: its role in tumorigenesis and ageing. J Cell Physiol. 2007;210:567–74.PubMedCrossRef
25.
Herman S, Zurgil N, Deutsch M. Low dose methotrexate induces apoptosis with reactive oxygen species involvement in T lymphocytic cell lines to a greater extent than in monocytic lines. Inflamm Res. 2005;54:273–80.PubMedCrossRef
26.
Martin SA, McCarthy A, Barber LJ, Burgess DJ, Parry S, Lord CJ, et al. Methotrexate induces oxidative damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2. EMBO Mol Med. 2009;1:323–37.PubMedCrossRef
27.
Robaey P, Krajinovic M, Marcoux S, Moghrabi A. Pharmacogenetics of the neurodevelopmental impact of anticancer chemotherapy. Dev Disabil Res Rev. 2008;14:211–20.PubMedCrossRef
28.
Kinsella AR, Smith D, Pickard M. Resistance to chemotherapeutic antimetabolites: a function of salvage pathway involvement and cellular response to DNA damage. Br J Cancer. 1997;75:935–45.PubMedCrossRef
29.
Mariotto S, Miscusi M, Persichini T, Colasanti M, Suzuki H. Ageing-related role of nitric oxide in the brain. In: Straub RH, Mochegiani E, editors. The neuroendocrine immune network in ageing. Elsevier B.V., Amsterdam, The Netherlands; 2004. pp 291–300.
30.
Stuehr D, Pou S, Rosen GM. Oxygen reduction by nitric-oxide synthases. J Biol Chem. 2001;276:14533–6.PubMedCrossRef
31.
Cosentino F, Luscher TF. Tetrahydrobiopterin and endothelial nitric oxide synthase activity. Cariovascular Res. 1999;43:274–8.CrossRef
32.
Hasegawa H, Sawabe K, Nakanishi N, Wakasugi OK. Delivery of exogenous tetrahydrobiopterin (BH4) to cells of target organs: role of salvage pathway and uptake of its precursor in effective elevation of tissue BH4. Mol Genet Metab. 2005;86:S2–10.PubMedCrossRef
33.
Crabtree MJ, Tatham AL, Hale AB, Alp NJ, Channon KM. Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways. J Biol Chem. 2009;284:28128–36.PubMedCrossRef
34.
Fukumura D, Kashiwagi S, Jain RK. The role of nitric oxide in tumor progression. Nat Rev Cancer. 2006;6:521–34.PubMedCrossRef
35.
36.
Passos JF, von Zglinicki T. Oxygen free radicals in cell senescence: are they signal transducers? Free Radic Res. 2006;40:1277–83.PubMedCrossRef
37.
Passos JF, Saretzki G, Ahmed S, Richter T, Peters H, Wappler I, et al. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLOS. 2007;5:e110.CrossRef
38.
39.
Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol. 2010;6:347.PubMedCrossRef
40.
Iwasa H, Han J, Ishikawa F. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells. 2003;8:131–44.PubMedCrossRef
41.
Sauer H, Wartenberg M, Hescheler J. Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell Physiol Biochem. 2001;11:173–86.PubMedCrossRef
42.
Woo HA, Yim SH, Shin DH, Kang D, Yu DY, Rhee SG. Inactivation of peroxiredoxin I by phosphorylation allows localized H2O2 accumulation for cell signaling. Cell. 2010;140:517–28.PubMedCrossRef
43.
Choi K, Ryu SW, Song S, Choi H, Kang SW, Choi C. Caspase-dependent generation of reactive oxygen species in human astrocytoma cells contributes to resistance to TRAIL-mediated apoptosis. Cell Death Differ. 2010;17:833–45.PubMedCrossRef
44.
Delgado MA, Deretic V. Toll-like receptors in control of immunological autophagy. Cell Death Differ. 2009;16:976–83.PubMedCrossRef
45.
Scherz-Shouval R, Elazar Z. ROS, mitochondria and the regulation of autophagy. Trends Cell Biol. 2007;17:422–7.PubMedCrossRef
46.
Young ARJ, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JFJ, et al. Autophagy mediates the mitotic senescence transition. Genes Dev. 2009;23:798–803.PubMedCrossRef
47.
Zarubin T, Han J. Activation and signaling of the p38 MAP kinase pathway. Cell Res. 2005;15:11–8.PubMedCrossRef
48.
Cagnol S, Chambard JC. ERK and cell death: Mechanisms of ERK-induced cell death—apoptosis, autophagy and senescence. FEBS J. 2009;277:2–21.PubMedCrossRef
49.
Fumagali M, d’Adda di Fagagna F. SASPense and DDRama in cancer and ageing. Nat Cell Biol. 2009;11:921–3.CrossRef
50.
Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, et al. Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009;11:973–81.PubMedCrossRef
51.
Novakova Z, Hubackova S, Kosar M, Janderova-Rossmeislova L, Dobrovolna J, Vasicova P, et al. Cytokine expression and signaling in drug-induced cellular senescence. Oncogene. 2010;29:273–84.PubMedCrossRef
52.
53.
Abreu MT. Toll-like receptor signaling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol. 2010;10:131–43.PubMedCrossRef
54.
Tesniere A, Panaretakis T, Kepp O, Apetoh L, Ghiringhelli F, Zitvogel L, et al. Molecular characteristics of immunogenic cancer cell death. Cell Death Differ. 2008;15:3–12.PubMedCrossRef
55.
Fridman AL, Tainsky MA. Critical pathways in cellular senescence and immortalization revealed by gene expression profiling. Oncogene. 2008;27:5975–87.PubMedCrossRef
56.
Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell. 2004;6:463–77.PubMedCrossRef
Metadata
Title
Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells
Authors
Magdalena Dabrowska
Marek Skoneczny
Wojciech Rode
Publication date
01-10-2011
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 5/2011
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-011-0198-x

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