Advertisement

Tumor Biology

, Volume 36, Issue 5, pp 3969–3977 | Cite as

Arsenic trioxide inhibits growth of human chondrosarcoma cells through G2/M arrest and apoptosis as well as autophagy

  • Guangjun Jiao
  • Tingting Ren
  • Wei Guo
  • Chongmin Ren
  • Kang Yang
Research Article

Abstract

It has been demonstrated that Gli1 is expressed in chondrosarcoma but not in the normal articular cartilage tissues. Downregulating Gli1 by small interfering RNA inhibited chondrosarcoma cells growth. Arsenic trioxide (ATO) has been demonstrated to suppress human cancer cell growth by targeting Gli1. The aim of this study was to investigate the effect of ATO on antineoplastic capability of chondrosarcoma cells. We found that ATO inhibited the growth of chondrosarcoma cells in dose-dependent and time-dependent manners via MTT and colony formation assays. In addition, ATO treatment induced apoptosis and promoted G2/M phase arrest in SW1353 cells as analyzed by flow cytometry assays and Western blotting. Furthermore, we observed that ATO also triggered autophagy by regulating mammalian target of rapamycin (mTOR) phosphorylation. Finally, we found that ATO-mediated cell death could be averted by autophagy inhibitor. Taken together, the current study suggested that ATO had therapeutic efficacy in human chondrosarcoma cells through the promotion of G2/M arrest and induction of both apoptosis as well as autophagy. ATO administration could be a novel therapeutic strategy for treating chondrosarcomas.

Keywords

Arsenic trioxide Chondrosarcoma Gli G2/M arrest Apoptosis Autophagy 

Notes

Acknowledgments

This work was supported by the Natural Science Foundation of China (No. 81172543) and the Specialised Research Fund for the Doctoral Programme of Higher Education of China (No. 20130001110076).

Conflicts of interest

None

References

  1. 1.
    Lee FY, Mankin HJ, Fondren G, Gebhardt MC, Springfield DS, Rosenberg AE, et al. Chondrosarcoma of bone: an assessment of outcome. J Bone Joint Surg Am. 1999;81:326–38.CrossRefPubMedGoogle Scholar
  2. 2.
    Bovee JV, Cleton-Jansen AM, Taminiau AH, Hogendoorn PC. Emerging pathways in the development of chondrosarcoma of bone and implications for targeted treatment. Lancet Oncol. 2005;6:599–607.CrossRefPubMedGoogle Scholar
  3. 3.
    Gelderblom H, Hogendoorn PC, Dijkstra SD, van Rijswijk CS, Krol AD, Taminiau AH, et al. The clinical approach towards chondrosarcoma. Oncologist. 2008;13:320–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Bauer HC, Brosjo O, Kreicbergs A, Lindholm J. Low risk of recurrence of enchondroma and low-grade chondrosarcoma in extremities. 80 patients followed for 2–25 years. Acta Orthop Scand. 1995;66:283–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Nybakken K, Perrimon N. Hedgehog signal transduction: recent findings. Curr Opin Genet Dev. 2002;12:503–11.CrossRefPubMedGoogle Scholar
  6. 6.
    Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15:3059–87.CrossRefPubMedGoogle Scholar
  7. 7.
    Ruiz i Altaba A, Sanchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2002;2:361–72.CrossRefPubMedGoogle Scholar
  8. 8.
    Lum L, Beachy PA. The hedgehog response network: sensors, switches, and routers. Science. 2004;304:1755–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, et al. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391:90–2.CrossRefPubMedGoogle Scholar
  10. 10.
    Lam CW, Xie J, To KF, Ng HK, Lee KC, Yuen NW, et al. A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene. 1999;18:833–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Roberts WM, Douglass EC, Peiper SC, Houghton PJ, Look AT. Amplification of the gli gene in childhood sarcomas. Cancer Res. 1989;49:5407–13.PubMedGoogle Scholar
  12. 12.
    Khatib ZA, Matsushime H, Valentine M, Shapiro DN, Sherr CJ, Look AT. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res. 1993;53:5535–41.PubMedGoogle Scholar
  13. 13.
    Zwerner JP, Joo J, Warner KL, Christensen L, Hu-Lieskovan S, Triche TJ, et al. The EWS/FLI1 oncogenic transcription factor deregulates GLI1. Oncogene. 2008;27:3282–91.CrossRefPubMedGoogle Scholar
  14. 14.
    Beauchamp E, Bulut G, Abaan O, Chen K, Merchant A, Matsui W, et al. Gli1 is a direct transcriptional target of EWS-FLI1 oncoprotein. J Biol Chem. 2009;284:9074–82.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sun Y, Guo W, Ren T, Liang W, Zhou W, Lu Q, et al. Gli1 inhibition suppressed cell growth and cell cycle progression and induced apoptosis as well as autophagy depending on ERK1/2 activity in human chondrosarcoma cells. Cell Death Dis. 2014;5:e979.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Cohen KJ, Gibbs IC, Fisher PG, Hayashi RJ, Macy ME, Gore L. A phase i trial of arsenic trioxide chemoradiotherapy for infiltrating astrocytomas of childhood. Neuro-Oncology. 2013;15:783–7.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Chen G, Wang K, Yang BY, Tang B, Chen JX, Hua ZC. Synergistic antitumor activity of oridonin and arsenic trioxide on hepatocellular carcinoma cells. Int J Oncol. 2012;40:139–47.PubMedGoogle Scholar
  18. 18.
    Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee YC, et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011;121:148–60.CrossRefPubMedGoogle Scholar
  19. 19.
    Kim J, Aftab BT, Tang JY, Kim D, Lee AH, Rezaee M, et al. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell. 2013;23:23–34.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kim J, Lee JJ, Gardner D, Beachy PA. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci U S A. 2010;107:13432–7.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Feng Y, Ke C, Tang Q, Dong H, Zheng X, Lin W, et al. Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis. 2014;5:e1088.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Tingting R, Wei G, Changliang P, Xinchang L, Yi Y. Arsenic trioxide inhibits osteosarcoma cell invasiveness via MAPK signaling pathway. Cancer Biol Ther. 2010;10:251–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Kerl K, Moreno N, Holsten T, Ahlfeld J, Mertins J, Hotfilder M, et al. Arsenic trioxide inhibits tumor cell growth in malignant rhabdoid tumors in vitro and in vivo by targeting overexpressed Gli1. Int J Cancer J Int Du Cancer. 2014;135:989–95.CrossRefGoogle Scholar
  24. 24.
    Nakamura S, Nagano S, Nagao H, Ishidou Y, Yokouchi M, Abematsu M, et al. Arsenic trioxide prevents osteosarcoma growth by inhibition of GLI transcription via DNA damage accumulation. PLoS One. 2013;8:e69466.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Sun K, Guo XL, Zhao QD, Jing YY, Kou XR, Xie XQ, et al. Paradoxical role of autophagy in the dysplastic and tumor-forming stages of hepatocarcinoma development in rats. Cell Death Dis. 2013;4:e501.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    White DE, Kurpios NA, Zuo D, Hassell JA, Blaess S, Mueller U, et al. Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell. 2004;6:159–70.CrossRefPubMedGoogle Scholar
  27. 27.
    Goussetis DJ, Platanias LC. Arsenic trioxide and the phosphoinositide 3-kinase/akt pathway in chronic lymphocytic leukemia. Clin Cancer Res : Off J Am Assoc Cancer Res. 2010;16:4311–2.CrossRefGoogle Scholar
  28. 28.
    Stevens JJ, Graham B, Walker AM, Tchounwou PB, Rogers C. The effects of arsenic trioxide on DNA synthesis and genotoxicity in human colon cancer cells. Int J Environ Res Public Health. 2010;7:2018–32.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Xia J, Li Y, Yang Q, Mei C, Chen Z, Bao B, et al. Arsenic trioxide inhibits cell growth and induces apoptosis through inactivation of notch signaling pathway in breast cancer. Int J Mol Sci. 2012;13:9627–41.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ding D, Lim KS, Eberhart CG. Arsenic trioxide inhibits Hedgehog, Notch and stem cell properties in glioblastoma neurospheres. Acta Neuropathol Commun. 2014;2:31.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Chiu HW, Ho YS, Wang YJ. Arsenic trioxide induces autophagy and apoptosis in human glioma cells in vitro and in vivo through downregulation of survivin. J Mol Med (Berl). 2011;89:927–41.CrossRefGoogle Scholar
  32. 32.
    Kawabe T. G2 checkpoint abrogators as anticancer drugs. Mol Cancer Ther. 2004;3:513–9.PubMedGoogle Scholar
  33. 33.
    Pereira DL, Dos Santos Ferreira AC, de Faria GP, Kwee JK. Autophagy interplays with apoptosis and cell cycle regulation in the growth inhibiting effect of trisenox in hep-2, a laryngeal squamous cancer. Pathology oncology research : POR 2014.Google Scholar
  34. 34.
    Li Y, Qu X, Qu J, Zhang Y, Liu J, Teng Y, et al. Arsenic trioxide induces apoptosis and G2/M phase arrest by inducing Cbl to inhibit PI3K/Akt signaling and thereby regulate p53 activation. Cancer Lett. 2009;284:208–15.CrossRefPubMedGoogle Scholar
  35. 35.
    Liu Q, Hilsenbeck S, Gazitt Y. Arsenic trioxide-induced apoptosis in myeloma cells: P53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/trail. Blood. 2003;101:4078–87.CrossRefPubMedGoogle Scholar
  36. 36.
    Liu N, Tai S, Ding B, Thor RK, Bhuta S, Sun Y, et al. Arsenic trioxide synergizes with everolimus (Rad001) to induce cytotoxicity of ovarian cancer cells through increased autophagy and apoptosis. Endocr Relat Cancer. 2012;19:711–23.CrossRefPubMedGoogle Scholar
  37. 37.
    Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007;67:6745–52.CrossRefPubMedGoogle Scholar
  38. 38.
    Deng XS, Wang S, Deng A, Liu B, Edgerton SM, Lind SE, et al. Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle. 2012;11:367–76.CrossRefPubMedGoogle Scholar
  39. 39.
    Carson DA, Ribeiro JM. Apoptosis and disease. Lancet. 1993;341:1251–4.CrossRefPubMedGoogle Scholar
  40. 40.
    Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: Crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8:741–52.CrossRefPubMedGoogle Scholar
  41. 41.
    Bhutia SK, Kegelman TP, Das SK, Azab B, Su ZZ, Lee SG, et al. Astrocyte elevated gene-1 induces protective autophagy. Proc Natl Acad Sci U S A. 2010;107:22243–8.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Dalby KN, Tekedereli I, Lopez-Berestein G, Ozpolat B. Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer. Autophagy. 2010;6:322–9.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Zhou F, Yang Y, Xing D. Bcl-2 and Bcl-xL play important roles in the crosstalk between autophagy and apoptosis. FEBS J. 2011;278:403–13.CrossRefPubMedGoogle Scholar
  44. 44.
    Bigelow RL, Chari NS, Unden AB, Spurgers KB, Lee S, Roop DR, et al. Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1. J Biol Chem. 2004;279:1197–205.CrossRefPubMedGoogle Scholar
  45. 45.
    Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, Philpott MP, et al. Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res. 2004;64:7724–31.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Guangjun Jiao
    • 1
  • Tingting Ren
    • 1
  • Wei Guo
    • 1
  • Chongmin Ren
    • 1
  • Kang Yang
    • 1
  1. 1.Musculoskeletal Tumor CenterPeking University People’s HospitalBeijingPeople’s Republic of China

Personalised recommendations