Abstract
Purpose
Senescence and cell death are fail-safe mechanisms protecting against tumorigenesis. Both these forms of cellular response could be induced in cancer cells, thus suppressing tumor progression. Therefore, to fully understand chemotherapeutic effects, not only symptoms of cell death, but also of senescence should be evaluated. Since the involvement of cytoskeleton components in these processes has been reported, changes in the organization and level of some cytoskeletal proteins may be indicative of cell fate.
Methods
We analyzed selected markers of senescence and cell death, including possible alterations in vimentin and G-actin cytoskeleton in A549 cells after treatment with doxorubicin. Light (SA-β-galactosidase), fluorescent (vimentin and G-actin labeling) and electron microscopic examinations along with flow cytometry methods (TUNEL, Annexin V/PI staining, cell cycle analysis, intracellular level of vimentin) were employed to determine the outcome of the treatment.
Results
Uncoupling between senescent cell morphology and stable cell cycle arrest occurred. Some differences in the organization and level of cytoskeletal proteins, especially of vimentin, like fluctuations in its level, were observed. On the other hand, G-actin seemed to be more stable than vimentin.
Conclusions
G-actin stability may imply its potential usefulness for permanent senescence detection. Along with slight to moderate cytoskeletal alterations, the obtained results suggest transient senescence-like state induction, followed by morphology typical of mitotic catastrophe in part of the A549 cells.
Similar content being viewed by others
References
Akisaka T, Yoshida H, Inoue S, Shimizu K (2001) Organization of cytoskeletal F-actin, G-actin, and gelsolin in the adhesion structures in cultured osteoclast. J Bone Miner Res 16:1248–1255. doi:10.1359/jbmr.2001.16.7.1248
Amaravadi RK, Thompson CB (2007) The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin Cancer Res 13:7271–7279. doi:10.1158/1078-0432.CCR-07-1595
Arthur CR, Gupton JT, Kellogg GE, Yeudall WA, Cabot MC, Newsham IF, Gewirtz DA (2007) Autophagic cell death, polyploidy and senescence induced in breast tumor cells by the substituted pyrrole JG-03–14, a novel microtubule poison. Biochem Pharmacol 74:981–991. doi:10.1016/j.bcp.2007.07.003
Ashcroft M, Vousden KH (1999) Regulation of p53 stability. Oncogene 18:7637–7643. doi:10.1038/sj.onc.1203012
Beauséjour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, Campisi J (2003) Reversal of human senescence: roles of the p53 and p16 pathways. EMBO J 22:4212–4222. doi:10.1093/emboj/cdg417
Binaschi M, Capranico G, Dal Bo L, Zunino F (1997) Relationship between lethal effects and topoisomerase II mediated double-strand DNA breaks produced by anthracyclines with different sequence specificity. Mol Pharmacol 51:1053–1059
Bird J, Ostler EL, Faragher RGA (2003) Can we say that senescent cells cause ageing? Exp Gerontol 38:1319–1326. doi:10.1016/j.exger.2003.09.011
Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, Stein H, Dörken B, Jenuwein T, Schmitt CA (2005) Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436:660–665. doi:10.1038/nature03841
Brookes S, Rowe J, Gutierrez Del Arroyo A, Bond J, Peters G (2004) Contribution of p16INK4a to replicative senescence of human fibroblasts. Exp Cell Res 298:549–559. doi:10.1016/j.yexcr.2004.04.035
Bursch W, Hochegger K, Török L, Marian B, Ellinger A, Hermann RS (2000) Autophagic and apoptotic types of programmed cell death exhibit different fates of cytoskeletal filaments. J Cell Sci 113:1189–1198
Byun Y, Chen F, Chang R, Trivedi M, Green KJ, Cryns VL (2001) Caspase cleavage of vimentin disrupts intermediate filaments and promotes apoptosis. Cell Death Differ 8:443–450. doi:10.1038/sj.cdd.4400840
Cao LG, Fishkind DJ, Wang YL (1993) Localization and dynamics of nonfilamentous actin in cultured cells. J Cell Biol 123:173–181. doi:10.1083/jcb.123.1.173
Chang B-D, Swift ME, Shen M, Fang J, Broude EV, Roninson IB (2002) Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent. Proc Natl Acad Sci USA 99:389–394. doi:10.1073/pnas.012602599
Chen Z, Trotman LC, Shaffer D, Lin H-K, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436:725–730. doi:10.1038/nature03918
Colombo R, Necco A, Vailati G, Milzani A (1988) Dose-dependence of doxorubicin effect on actin assembly in vitro. Exp Mol Pathol 49:297–304. doi:10.1016/0014-4800(88)90002-0
Crescenzi E, Palumbo G, Brady HJM (2003) Bcl-2 activates a programme of premature senescence in human carcinoma cells. Biochem J 375:263–274. doi:10.1042/BJ20030868
Crescenzi E, Palumbo G, Brady HJM (2005) Roscovitine modulates DNA repair and senescence: implications for combination chemotherapy. Clin Cancer Res 11:8158–8171. doi:10.1158/1078-0432.CCR-05-1042
Croce MV, Colussi AG, Price MR, Segal-Eiras A (1999) Identification and characterization of different subpopulations in a human lung adenocarcinoma cell line (A549). Pathol Oncol Res 5:197–204. doi:10.1053/paor.1999.0212
Di Felice V, Ardizzone N, Marcianò V, Bartolotta T, Cappello F, Farina F, Zummo G (2005) Senescence-associated HSP60 expression in normal human skin fibroblasts. Anat Rec Discov Mol Cell Evol Biol A 284:446–453
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367. doi:10.1073/pnas.92.20.9363
Dimri GP, Itahana K, Acosta M, Campisi J (2000) Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14ARF tumor suppressor. Mol Cell Biol 20:273–285
Dinsdale D, Lee JC, Dewson G, Cohen GM, Peter ME (2004) Intermediate filaments control the intracellular distribution of caspases during apoptosis. Am J Pathol 164:395–407
Douarre C, Gomez D, Morjani H, Zahm JM, O’donohue MF, Eddabra L, Mailliet P, Riou JF, Trentesaux C (2005) Overexpression of Bcl-2 is associated with apoptotic resistance to the G-quadruplex ligand 12459 but is not sufficient to confer resistance to long-term senescence. Nucleic Acids Res 33:2192–2203. doi:10.1093/nar/gki514
Dulić V, Beney G-E, Frebourg G, Drullinger LF, Stein GH (2000) Uncoupling between phenotypic senescence and cell cycle arrest in aging p21-deficient fibroblasts. Mol Cell Biol 20:6741–6754
Dunaief JL, Strober BE, Guha S, Khavari PA, Alin K, Luban J, Begemann M, Crabtree GR, Goff SP (1994) The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell 79:119–130. doi:10.1016/0092-8674(94)90405-7
Edelman MJ, Quam H, Mullins B (2001) Interactions of gemcitabine, carboplatin and paclitaxel in molecularly defined non-small-cell lung cancer cell lines. Cancer Chemother Pharmacol 48:141–144. doi:10.1007/s002800000273
Eom Y-W, Kim MA, Park SS, Goo MJ, Kwon HJ, Sohn S, Kim W-H, Yoon G, Choi KS (2005) Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype. Oncogene 24:4765–4777. doi:10.1038/sj.onc.1208627
Eulitz D, Mannherz HG (2007) Inhibition of deoxyribonuclease I by actin is to protect cells from premature cell death. Apoptosis 12:1511–1521. doi:10.1007/s10495-007-0078-4
Fang L, Igarashi M, Leung J, Sugrue MM, Lee SW, Aaronson SA (1999) p21Waf1/Cip1/Sdi1 induces permanent growth arrest with markers of replicative senescence in human tumor cells lacking functional p53. Oncogene 18:2789–2797. doi:10.1038/sj.onc.1202615
Feldser DM, Greider CW (2007) Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell 11:461–469. doi:10.1016/j.ccr.2007.02.026
Filyak Y, Filyak O, Stoika R (2007) Transforming growth factor beta-1 enhances cytotoxic effect of doxorubicin in human lung adenocarcinoma cells of A549 line. Cell Biol Int 31:851–855. doi:10.1016/j.cellbi.2007.02.008
Filyak Y, Filyak O, Souchelnytskyi S, Stoika R (2008) Doxorubicin inhibits TGF-β signaling in human lung carcinoma A549 cells. Eur J Pharmacol 590:67–73. doi:10.1016/j.ejphar.2008.05.030
Foster KA, Oster CG, Mayer MM, Avery ML, Audus KL (1998) Characterization of the A549 cell line as a type II pulmonary epithelial cell model for drug metabolism. Exp Cell Res 243:359–366. doi:10.1006/excr.1998.4172
Giard DJ, Aaronson SA, Todaro GJ, Arnstein P, Kersey JH, Dosik H, Parks WP (1973) In vitro cultivation of human tumors: establishment of cell lines derived from a series of solid tumors. J Natl Cancer Inst 51:1417–1423
Grzanka A, Grzanka D, Orlikowska M (2003) Cytoskeletal reorganization during process of apoptosis induced by cytostatic drugs in K-562 and HL-60 leukemia cell lines. Biochem Pharmacol 66:1611–1617. doi:10.1016/S0006-2952(03)00532-X
Guénal I, Risler Y, Mignotte B (1997) Down-regulation of actin genes precedes microfilament network disruption and actin cleavage during p53-mediated apoptosis. J Cell Sci 110:489–495
Hatcher EL, Alexander JM, Kang YJ (1997) Decreased sensitivity to adriamycin in cadmium-resistant human lung carcinoma A549 cells. Biochem Pharmacol 53:747–754. doi:10.1016/S0006-2952(96)00811-8
Haynes A, Shaik MS, Chatterjee A, Singh M (2003) Evaluation of an aerosolized selective COX-2 inhibitor as a potentiator of doxorubicin in a non-small-cell lung cancer cell line. Pharm Res 20:1485–1495. doi:10.1023/A:1025774630993
He Y, Fan S, Jiang Y (2005) p73 gene overexpression induces apoptosis and increases chemosensitivity in human lung adenocarcinoma cells A549. Int J Oncol 3:1
Hoffman PC, Mauer AM, Vokes EE (2000) Lung cancer. Lancet 355:479–485
Hukkanen J, Lassila A, Päivärinta K, Valanne S, Sarpo S, Hakkola J, Pelkonen O, Raunio H (2000) Induction and regulation of xenobiotic-metabolizing cytochrome P450 s in the human A549 lung adenocarcinoma cell line. Am J Respir Cell Mol Biol 22:360–366
Iavarone A, Massagué J (1997) Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-β in cells lacking the CDK inhibitor p15. Nature 387:417–422. doi:10.1038/387417a0
Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91:649–659. doi:10.1016/S0092-8674(00)80452-3
Katakura Y, Nakata E, Miura T, Shirahata S (1999) Transforming growth factor β triggers two independent-senescence programs in cancer cells. Biochem Biophys Res Commun 255:110–115. doi:10.1006/bbrc.1999.0129
Klein LE, Freeze BS, Smith AB, Horwitz SB (2005) The microtubule stabilizing agent discodermolide is a potent inducer of accelerated senescence. Cell Cycle 4:501–507
Kurz DJ, Decary S, Hong Y, Erusalimsky JD (2000) Senescence-associated β-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci 113:3613–3622
Kwak IH, Kim HS, Choi OR, Ryu MS, Lim IK (2004) Nuclear accumulation of globular actin as a cellular senescence marker. Cancer Res 64:572–580. doi:10.1158/0008-5472.CAN-03-1856
Lee BY, Han JA, Im JS, Morrone A, Johung K, Goodwin EC, Kleijer WJ, DiMaio D, Hwang ES (2006) Senescence-associated β-galactosidase is lysosomal β-galactosidase. Aging Cell 5:187–195. doi:10.1111/j.1474-9726.2006.00199.x
Lieber M, Smith B, Szakal A, Nelson-Rees W, Todaro G (1976) A continuous tumor-cell line from a human lung carcinoma with properties of type II alveolar epithelial cells. Int J Cancer 17:62–70. doi:10.1002/ijc.2910170110
Lim IK, Hong KW, Kwak IH, Yoon G, Park SC (2000) Cytoplasmic retention of p-Erk1/2 and nuclear accumulation of actin proteins during cellular senescence in human diploid fibroblasts. Mech Ageing Dev 119:113–129. doi:10.1016/S0047-6374(00)00167-6
Liu Y, El-Naggar S, Darling DS, Higashi Y, Dean DC (2008) Zeb1 links epithelial-mesenchymal transition and cellular senescence. Development 135:579–588. doi:10.1242/dev.007047
Lock RB, Stribinskiene L (1996) Dual modes of death induced by etoposide in human epithelial tumor cells allow Bcl-2 to inhibit apoptosis without affecting clonogenic survival. Cancer Res 56:4006–4012
Lockshin RA, Zakeri Z (2004) Apoptosis, autophagy, and more. Int J Biochem Cell Biol 36:2405–2419. doi:10.1016/j.biocel.2004.04.011
Mashima T, Naito M, Noguchi K, Miller DK, Nicholson DW, Tsuruo T (1997) Actin cleavage by CPP-32/apopain during the development of apoptosis. Oncogene 14:1007–1012. doi:10.1038/sj.onc.1200919
Meijerman I, Blom WM, de Bont HJGM, Mulder GJ, Nagelkerke JF (1997) Nuclear accumulation of G-actin in isolated rat hepatocytes by adenine nucleotides. Biochem Biophys Res Commun 240:697–700. doi:10.1006/bbrc.1997.7724
Meijerman I, Blom WM, de Bont HJGM, Mulder GJ, Nagelkerke JF (1999) Induction of apoptosis and changes in nuclear G-actin are mediated by different pathways: the effect of inhibitors of protein and RNA synthesis in isolated rat hepatocytes. Toxicol Appl Pharmacol 156:46–55. doi:10.1006/taap.1998.8616
Meriwether WD, Bachur NR (1972) Inhibition of DNA and RNA metabolism by daunorubicin and adriamycin in L1210 mouse leukemia. Cancer Res 32:1137–1142
Mi J, Zhang X, Rabbani ZN, Liu Y, Reddy SK, Su Z, Salahuddin FK, Viles K, Giangrande PH, Dewhirst MW, Sullenger BA, Kontos CD, Clary BM (2008) RNA aptamer-targeted inhibition of NF-κB suppresses non-small cell lung cancer resistance to doxorubicin. Mol Ther 16:66–73. doi:10.1038/sj.mt.6300320
Michaloglou C, Vredeveld LCW, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS (2005) BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436:720–724. doi:10.1038/nature03890
Michishita E, Nakabayashi K, Ogino H, Suzuki T, Fujii M, Ayusawa D (1998) DNA topoisomerase inhibitors induce reversible senescence in normal human fibroblasts. Biochem Biophys Res Commun 253:667–671. doi:10.1006/bbrc.1998.9832
Milzani A, Rossi R, Di Simplicio P, Giustarini D, Colombo R, DalleDonne I (2000) The oxidation produced by hydrogen peroxide on Ca-ATP-G-actin. Protein Sci 9:1774–1782. doi:10.1110/ps.9.9.1774
Mishima K, Handa JT, Aotaki-Keen A, Lutty GA, Morse LS, Hjelmeland LM (1999) Senescence-associated β-galactosidase histochemistry for the primate eye. Invest Ophthalmol Vis Sci 40:1590–1593
Moll UM, Ostermeyer AG, Haladay R, Winkfield B, Frazier M, Zambetti G (1996) Cytoplasmic sequestration of wild-type p53 protein impairs the G1 checkpoint after DNA damage. Mol Cell Biol 16:1126–1137
Mortenson MM, Schlieman MG, Virudachalam S, Bold RJ (2004) Effects of the proteasome inhibitor bortezomib alone and in combination with chemotherapy in the A549 non-small-cell lung cancer cell line. Cancer Chemother Pharmacol 54:343–353. doi:10.1007/s00280-004-0811-4
Moxham BL, Webb PP, Benjamin M, Ralphs JR (1998) Changes in the cytoskeleton of cells within the periodontal ligament and dental pulp of the rat first molar tooth during ageing. Eur J Oral Sci 106(Suppl 1):376–383
Nakanishi K, Maruyama M, Shibata T, Morishima N (2001) Identification of a caspase-9 substrate and detection of its cleavage in programmed cell death during mouse development. J Biol Chem 276:41237–41244. doi:10.1074/jbc.M105648200
Narita M, Nũnez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113:703–716. doi:10.1016/S0092-8674(03)00401-X
Nishio K, Inoue A (2005) Senescence-associated alterations of cytoskeleton: extraordinary production of vimentin that anchors cytoplasmic p53 in senescent human fibroblasts. Histochem Cell Biol 123:263–273. doi:10.1007/s00418-005-0766-5
Nishio K, Inoue A, Qiao S, Kondo H, Mimura A (2001) Senescence and cytoskeleton: overproduction of vimentin induces senescent-like morphology in human fibroblasts. Histochem Cell Biol 116:321–327. doi:10.1007/s004180100325
Okamoto A, Hussain SP, Hagiwara K, Spillare EA, Rusin MR, Demetrick DJ, Serrano M, Hannon GJ, Shiseki M, Zariwala M, Xiong Y, Beach DH, Yokota J, Harris CC (1995) Mutations in the p16 INK4/MTS1/CDKN2, p15 INK4B/MTS2, and p18 genes in primary and metastatic lung cancer. Cancer Res 55:1448–1451
Olave IA, Reck-Peterson SL, Crabtree GR (2002) Nuclear actin and actin-related proteins in chromatin remodeling. Annu Rev Biochem 71:755–781. doi:10.1146/annurev.biochem.71.110601.135507
Otterson GA, Villalona-Calero MA, Sharma S, Kris MG, Imondi A, Gerber M, White DA, Ratain MJ, Schiller JH, Sandler A, Kraut M, Mani S, Murren JR (2007) Phase I study of inhaled doxorubicin for patients with metastatic tumors to the lungs. Clin Cancer Res 13:1246–1252. doi:10.1158/1078-0432.CCR-06-1096
Parkin MD (2001) Global cancer statistics in the year 2000. Lancet Oncol 2:533–543. doi:10.1016/S1470-2045(01)00486-7
Patlakas G, Bouros D, Tsantekidou-Pozova S, Koukourakis MI (2005) Triplet chemotherapy with docetaxel, gemcitabine and liposomal doxorubicin, supported with subcutaneous amifostine and hemopoietic growth factors, in advanced non-small cell lung cancer. Anticancer Res 25:1427–1431
Pendleton A, Pope B, Weeds A, Koffer A (2003) Latrunculin B or ATP depletion induces cofilin-dependent translocation of actin into nuclei of mast cells. J Biol Chem 278:14394–14400. doi:10.1074/jbc.M206393200
Pronzato P, Vigani A, Tognoni A, Vaira F, Canessa P (2001) Anthracyclines in non-small cell lung cancer. Lung Cancer 34:S57–S59. doi:10.1016/S0169-5002(01)00394-4
Rando OJ, Zhao K, Janmey P, Crabtree GR (2002) Phosphatidylinositol-dependent actin filament binding by the SWI/SNF-like BAF chromatin remodeling complex. Proc Natl Acad Sci USA 99:2824–2829. doi:10.1073/pnas.032662899
Rebbaa A (2005) Targeting senescence pathways to reverse drug resistance in cancer. Cancer Lett 219:1–13. doi:10.1016/j.canlet.2004.08.011
Rebbaa A, Zheng X, Chou PM, Mirkin BL (2003) Caspase inhibition switches doxorubicin-induced apoptosis to senescence. Oncogene 22:2805–2811. doi:10.1038/sj.onc.1206366
Riou JF, Guittat L, Mailliet P, Laoui A, Renou E, Petitgenet O, Mégnin-Chanet F, Hélène C, Mergny JL (2002) Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands. Proc Natl Acad Sci USA 99:2672–2677. doi:10.1073/pnas.052698099
Roberson RS, Kussick SJ, Vallieres E, Chen SY, Wu DY (2005) Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res 65:2795–2803. doi:10.1158/0008-5472.CAN-04-1270
Safiejko-Mroczka B, Bell PB (1998) Distribution of cytoskeletal proteins in neomycin-induced protrusions of human fibroblasts. Exp Cell Res 242:495–514. doi:10.1006/excr.1997.3871
Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM, Lowe SW (2002) A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109:335–346. doi:10.1016/S0092-8674(02)00734-1
Seluanov A, Gorbunova V, Falcovitz A, Sigal A, Milyavsky M, Zurer I, Shohat G, Goldfinger N, Rotter V (2001) Change of the death pathway in senescent human fibroblasts in response to DNA damage is caused by an inability to stabilize p53. Mol Cell Biol 21:1552–1564. doi:10.1128/MCB.21.5.1552-1564.2001
Sherwood SW, Rush D, Ellsworth JL, Schimke RT (1988) Defining cellular senescence in IMR-90 cells: a flow cytometric analysis. Proc Natl Acad Sci USA 85:9086–9090. doi:10.1073/pnas.85.23.9086
Sommers CL, Heckford SE, Skerker JM, Worland P, Torri JA, Thompson EW, Byers SW, Gelmann EP (1992) Loss of epithelial markers and acquisition of vimentin expression in adriamycin- and vinblastine-resistant human breast cancer cell lines. Cancer Res 52:5190–5197
Spira A, Ettinger DS (2004) Multidisciplinary management of lung cancer. N Engl J Med 350:379–392. doi:10.1056/NEJMra035536
Stein GH, Drullinger LF, Soulard A, Dulić V (1999) Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol 19:2109–2117
Sung J-M, Cho H-J, Yi H, Lee CH, Kim HS, Kim DK, Abd El-Aty AM, Kim JS, Landowski CP, Hediger MA, Shin HC (2008) Characterization of a stem cell population in lung cancer A549 cells. Biochem Biophys Res Commun 371:163–167. doi:10.1016/j.bbrc.2008.04.038
te Poele RH, Okorokov AL, Jardine L, Cummings J, Joel SP (2002) DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res 62:1876–1883
Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N, Iwata KK, Gibson N, Haley JD (2005) Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res 65:9455–9462. doi:10.1158/0008-5472.CAN-05-1058
Tolstonog GV, Shoeman RL, Traub U, Traub P (2001) Role of the intermediate filament protein vimentin in delaying senescence and in the spontaneous immortalization of mouse embryo fibroblasts. DNA Cell Biol 20:509–529. doi:10.1089/104454901317094945
Untergasser G, Koch HB, Menssen A, Hermeking H (2002) Characterization of epithelial senescence by serial analysis of gene expression: identification of genes potentially involved in prostate cancer. Cancer Res 62:6255–6262
Van der Loo B, Fenton MJ, Erusalimsky JD (1998) Cytochemical detection of a senescence-associated β-galactosidase in endothelial and smooth muscle cells from human and rabbit blood vessels. Exp Cell Res 241:309–315. doi:10.1006/excr.1998.4035
Vartiainen MK, Guettler S, Larijani B, Treisman R (2007) Nuclear actin regulates dynamic, subcellular localization and activity of the SRF cofactor MAL. Science 316:1749–1752
Wada A, Fukuda M, Mishima M, Nishida E (1998) Nuclear export of actin: a novel mechanism regulating the subcellular localization of a major cytoskeletal protein. EMBO J 17:1635–1641. doi:10.1093/emboj/17.6.1635
Walen KH (2007) Origin of diplochromosomal polyploidy in near-senescent fibroblast cultures: Heterochromatin, telomeres and chromosomal instability (CIN). Cell Biol Int 31:1447–1455. doi:10.1016/j.cellbi.2007.06.015
Wang X, Wong SCH, Pan J, Tsao SW, Fung KHY, Kwong DLW, Sham JST, Nicholls JM (1998) Evidence of cisplatin-induced senescent-like growth arrest in nasopharyngeal carcinoma cells. Cancer Res 58:5019–5022
Węsierska-Gądek J, Wojciechowski J, Ranftler C, Schmid G (2005) Role of p53 tumor suppressor in ageing: regulation of transient cell cycle arrest and terminal senescence. J Physiol Pharmacol 56:15–28
Xie QC, Hu YD, Wang LL, Chen ZT, Diao XW, Wang ZX, Guan HJ, Zhu B, Sun JG, Duan YZ, Chen FL, Nian WQ (2005) The co-transfection of p16(INK4a) and p14(ARF) genes into human lung cancer cell line A549 and the effects on cell growth and chemosensitivity. Colloids Surf B Biointerfaces 46:188–196. doi:10.1016/j.colsurfb.2005.10.006
Yang D, McCrann DJ, Nguyen H, St Hilaire C, DePinho RA, Jones MR, Ravid K (2007) Increased polyploidy in aortic vascular smooth muscle cells during aging is marked by cellular senescence. Aging Cell 6:257–260. doi:10.1111/j.1474-9726.2007.00274.x
Zhang R, Chen W, Adams PD (2007) Molecular dissection of formation of senescence-associated heterochromatin foci. Mol Cell Biol 27:2343–2358. doi:10.1128/MCB.02019-06
Acknowledgments
We would like to acknowledge P. Kopiński, Ph.D. (Department of Gene Therapy, Ludwik Rydygier Collegium Medicum of Bydgoszcz, Nicolaus Copernicus University, Poland) for supplying A549 cells. This work was supported by the Grant UMK (Nicolaus Coprenicus University) no. 33/2008.
Conflict of interest statement
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Litwiniec, A., Grzanka, A., Helmin-Basa, A. et al. Features of senescence and cell death induced by doxorubicin in A549 cells: organization and level of selected cytoskeletal proteins. J Cancer Res Clin Oncol 136, 717–736 (2010). https://doi.org/10.1007/s00432-009-0711-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-009-0711-4