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Frontiers of Medicine

, Volume 8, Issue 2, pp 227–235 | Cite as

Reactive oxygen species generation is essential for cisplatininduced accelerated senescence in hepatocellular carcinoma

  • Kai Qu
  • Ting Lin
  • Zhixin Wang
  • Sinan Liu
  • Hulin Chang
  • Xinsen Xu
  • Fandi Meng
  • Lei Zhou
  • Jichao Wei
  • Minghui Tai
  • Yafeng Dong
  • Chang Liu
Research Article

Abstract

Accelerated senescence is important because this process is involved in tumor suppression and has been induced by many chemotherapeutic agents. The platinum-based chemotherapeutic agent cisplatin displays a wide range of antitumor activities. However, the molecular mechanism of cisplatin-induced accelerated senescence in hepatocellular carcinoma (HCC) remains unclear. In the present study, the growth inhibitory effect of cisplatin on HepG2 and SMMC-7721 cells was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cellular senescence was then assessed by β-galactosidase assay. Senescence-related factors, including p53, p21, and p16, were evaluated by quantitative reverse transcription-polymerase chain reaction. Reactive oxygen species (ROS) was analyzed by flow cytometry. Our results revealed that cisplatin reduced the proliferation of HepG2 and SMMC-7721 cells in a dose- and time-dependent manner. Senescent phenotype observed in cisplatintreated hepatoma cells was dependent on p53 and p21 activation but not on p16 activation. Furthermore, cisplatininduced accelerated senescence depended on intracellular ROS generation. The ROS scavenger N-acetyl-L-cysteine also significantly suppressed the cisplatin-induced senescence of HepG2 and SMMC-7721 cells. In conclusion, our results revealed a functional link between intracellular ROS generation and cisplatin-induced accelerated senescence, and this link may be used as a potential target of HCC.

Keywords

reactive oxygen species senescence cisplatin hepatocellular carcinoma 

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References

  1. 1.
    Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 1965; 37(3): 614–636PubMedCrossRefGoogle Scholar
  2. 2.
    Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92(20): 9363–9367PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Chang BD, Broude EV, Dokmanovic M, Zhu H, Ruth A, Xuan Y, Kandel ES, Lausch E, Christov K, Roninson IB. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res 1999; 59(15): 3761–3767PubMedGoogle Scholar
  4. 4.
    te Poele RH, Okorokov AL, Jardine L, Cummings J, Joel SP. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res 2002; 62(6): 1876–1883Google Scholar
  5. 5.
    Fang K, Chiu CC, Li CH, Chang YT, Hwang HT. Cisplatin-induced senescence and growth inhibition in human non-small cell lung cancer cells with ectopic transfer of p16INK4a. Oncol Res 2007; 16(10): 479–488PubMedCrossRefGoogle Scholar
  6. 6.
    Wang X, Wong SC, Pan J, Tsao SW, Fung KH, Kwong DL, Sham JS, Nicholls JM. Evidence of cisplatin-induced senescent-like growth arrest in nasopharyngeal carcinoma cells. Cancer Res 1998; 58(22): 5019–5022PubMedGoogle Scholar
  7. 7.
    Panieri E, Gogvadze V, Norberg E, Venkatesh R, Orrenius S, Zhivotovsky B. Reactive oxygen species generated in different compartments induce cell death, survival, or senescence. Free Radic Biol Med 2013; 57: 176–187PubMedCrossRefGoogle Scholar
  8. 8.
    Li SK, Smith DK, Leung WY, Cheung AM, Lam EW, Dimri GP, Yao KM. FoxM1c counteracts oxidative stress-induced senescence and stimulates Bmi-1 expression. J Biol Chem 2008; 283(24): 16545–16553PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Qu K, Xu X, Liu C, Wu Q, Wei J, Meng F, Zhou L, Wang Z, Lei L, Liu P. Negative regulation of transcription factor FoxM1 by p53 enhances oxaliplatin-induced senescence in hepatocellular carcinoma. Cancer Lett 2013; 331(1): 105–114PubMedCrossRefGoogle Scholar
  10. 10.
    Roberson RS, Kussick SJ, Vallieres E, Chen SY, Wu DY. Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res 2005; 65(7): 2795–2803PubMedCrossRefGoogle Scholar
  11. 11.
    Colavitti R, Finkel T. Reactive oxygen species as mediators of cellular senescence. IUBMB Life 2005; 57(4–5): 277–281PubMedCrossRefGoogle Scholar
  12. 12.
    Ishikawa F. Cellular senescence, an unpopular yet trustworthy tumor suppressor mechanism. Cancer Sci 2003; 94(11): 944–947PubMedCrossRefGoogle Scholar
  13. 13.
    Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, Benguría A, Zaballos A, Flores JM, Barbacid M, Beach D, Serrano M. Tumour biology: senescence in premalignant tumours. Nature 2005; 436(7051): 642PubMedCrossRefGoogle Scholar
  14. 14.
    Collado M, Serrano M. Senescence in tumours: evidence from mice and humans. Nat Rev Cancer 2010; 10(1): 51–57PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007; 445(7128): 656–660PubMedCrossRefGoogle Scholar
  16. 16.
    Jones KR, Elmore LW, Jackson-Cook C, Demasters G, Povirk LF, Holt SE, Gewirtz DA. p53-Dependent accelerated senescence induced by ionizing radiation in breast tumour cells. Int J Radiat Biol 2005; 81(6): 445–458PubMedCrossRefGoogle Scholar
  17. 17.
    Santarosa M, Del Col L, Tonin E, Caragnano A, Viel A, Maestro R. Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers. Mol Cancer Ther 2009; 8(4): 844–854PubMedCrossRefGoogle Scholar
  18. 18.
    Ozturk N, Erdal E, Mumcuoglu M, Akcali KC, Yalcin O, Senturk S, Arslan-Ergul A, Gur B, Yulug I, Cetin-Atalay R, Yakicier C, Yagci T, Tez M, Ozturk M. Reprogramming of replicative senescence in hepatocellular carcinoma-derived cells. Proc Natl Acad Sci USA 2006; 103(7): 2178–2183PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Petros WP, Broadwater G, Berry D, Jones RB, Vredenburgh JJ, Gilbert CJ, Gibbs JP, Colvin OM, Peters WP. Association of highdose cyclophosphamide, cisplatin, and carmustine pharmacokinetics with survival, toxicity, and dosing weight in patients with primary breast cancer. Clin Cancer Res 2002; 8(3): 698–705PubMedGoogle Scholar
  20. 20.
    Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM, Lowe SW. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 2002; 109(3): 335–346PubMedCrossRefGoogle Scholar
  21. 21.
    Chang BD, Xuan Y, Broude EV, Zhu H, Schott B, Fang J, Roninson IB. Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs. Oncogene 1999; 18(34): 4808–4818PubMedCrossRefGoogle Scholar
  22. 22.
    Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 2005; 436(7051): 725–730PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Rayess H, Wang MB, Srivatsan ES. Cellular senescence and tumor suppressor gene p16. Int J Cancer 2012; 130(8): 1715–1725PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Stein GH, Drullinger LF, Soulard A, Dulić V. Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol 1999; 19(3): 2109–2117PubMedCentralPubMedGoogle Scholar
  25. 25.
    Vigneron A, Vousden KH. p53, ROS and senescence in the control of aging. Aging (Albany NY) 2010; 2(8): 471–474Google Scholar
  26. 26.
    Lim SC, Choi JE, Kang HS, Han SI. Ursodeoxycholic acid switches oxaliplatin-induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53-caspase 8 pathway in HepG2 hepatocellular carcinoma. Int J Cancer 2010; 126(7): 1582–1595PubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Kai Qu
    • 1
  • Ting Lin
    • 1
    • 2
  • Zhixin Wang
    • 1
  • Sinan Liu
    • 1
  • Hulin Chang
    • 1
  • Xinsen Xu
    • 1
  • Fandi Meng
    • 1
  • Lei Zhou
    • 1
  • Jichao Wei
    • 1
  • Minghui Tai
    • 1
  • Yafeng Dong
    • 3
  • Chang Liu
    • 1
    • 2
  1. 1.Department of Hepatobiliary SurgeryXi’an Jiaotong UniversityXi’anChina
  2. 2.Surgical Intensive Care Unit, the First Affiliated Hospital, School of MedicineXi’an Jiaotong UniversityXi’anChina
  3. 3.Department of Obstetrics and GynecologyKansas UniversityKansas CityUSA

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