Skip to main content
SpringerLink
Log in

T0070907, a PPAR γ Inhibitor, Induced G2/M Arrest Enhances the Effect of Radiation in Human Cervical Cancer Cells Through Mitotic Catastrophe

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Overexpression of peroxisome proliferator activator receptor γ (PPARγ) has been implicated in many types of cancer including cervical cancer. Radiation therapy remains the main nonsurgical modality for the treatment of cervical cancer. The present study reports the impact of pharmacological inhibition of PPARγ in enhancing the radiosensitization of cervical cancer cells in vitro. Three cervical cancer cell lines (HeLa, SiHa, and Me180) were treated with a PPARγ inhibitor, T0070907, and/or radiation. The changes in protein, cell cycle, DNA content, apoptosis, and cell survival were analyzed. The PPARγ is differentially expressed in cervical cancer cells with maximum expression in ME180 cells. T0070907 has significantly decreased the tubulin levels in a time-dependent manner in ME180 cells. The decrease in the tubulin levels after T0070907 in ME180 and SiHa cells was associated with significant increase in the cells at the G2/M phase. The changes in the tubulin and G2/M phase were not evident in HeLa cells. T0070907 reduced the protein levels of PPARγ; however, PPARγ silencing had no effect on the α-tubulin level in ME180 cells suggesting the PPARγ-dependent and -independent actions of T0070907. To ascertain the impact of synergistic effect of T0070907 and radiation, HeLa and ME180 cells were pretreated with T0070907 and subjected to radiation (4 Gy). Annexin V-fluorescein isothiocyanate analysis revealed increased apoptosis in cells treated with radiation and T0070907 when compared to control and individual treatment. In addition, T0070907 pretreatment enhanced radiation-induced tetraploidization reinforcing the additive effect of T0070907. Confocal analysis of tubulin confirmed the onset of mitotic catastrophe in cells treated with T0070907 and radiation. These results strongly suggest the radiosensitizing effects of T0070907 through G2/M arrest and mitotic catastrophe.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    Article  PubMed  Google Scholar 

  2. Woodman CB, Collins SI, Young LS. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer. 2007;7(1):11–22.

    Article  CAS  PubMed  Google Scholar 

  3. Martelli ML, Iuliano R, Le Pera I, et al. Inhibitory effects of peroxisome proliferator-activated receptor gamma on thyroid carcinoma cell growth. J Clin Endocrinol Metab. 2002;87(10):4728–4735.

    Article  CAS  PubMed  Google Scholar 

  4. Panigrahy D, Shen LQ, Kieran MW, Kaipainen A. Therapeutic potential of thiazolidinediones as anticancer agents. Expert Opin Investig Drugs. 2003;12(12):1925–1937.

    Article  CAS  PubMed  Google Scholar 

  5. Han S, Inoue H, Flowers LC, Sidell N. Control of COX-2 gene expression through peroxisome proliferator-activated receptor gamma in human cervical cancer cells. Clin Cancer Res. 2003; 9(12):4627–4635.

    CAS  PubMed  Google Scholar 

  6. Posch MG, Zang C, Mueller W, Lass U, von Deimling A, Elstner E. Somatic mutations in peroxisome proliferator-activated receptor-gamma are rare events in human cancer cells. Med Sci Monit. 2004;10(8):BR250–BR254.

    CAS  PubMed  Google Scholar 

  7. Lefebvre AM, Chen I, Desreumaux P, et al. Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat Med. 1998;4(9): 1053–1057.

    Article  CAS  PubMed  Google Scholar 

  8. Saez E, Tontonoz P, Nelson MC, et al. Activators of the nuclear receptor PPARgamma enhance colon polypformation. Nat Med. 1998;4(9):1058–1061.

    Article  CAS  PubMed  Google Scholar 

  9. Kristiansen G, Jacob J, Buckendahl AC, et al. Peroxisome proliferator-activated receptor gamma is highly expressed in pancreatic cancer and is associated with shorter overall survival times. Clin Cancer Res. 2006;12(21):6444–6451.

    Article  CAS  PubMed  Google Scholar 

  10. Schaefer KL, Takahashi H, Morales VM, et al. PPARgamma inhibitors reduce tubulin protein levels by a PPARgamma, PPARdelta and proteasome-independent mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cells. Int J Cancer. 2007;120(3):702–713.

    Article  CAS  PubMed  Google Scholar 

  11. Lee G, Elwood F, McNally J, et al. T0070907, a selective ligand for peroxisome proliferator-activated receptor gamma, functions as an antagonist of biochemical and cellular activities. J Biol Chem. 2002;277(22):19649–19657.

    Article  CAS  PubMed  Google Scholar 

  12. Nakajima A, Tomimoto A, Fujita K, et al. Inhibition of peroxisome proliferator-activated receptor gamma activity suppresses pancreatic cancer cell motility. Cancer Sci. 2008;99(10):1892–900.

    Article  CAS  PubMed  Google Scholar 

  13. Takahashi H, Fujita K, Fujisawa T, et al. Inhibition of peroxisome proliferator-activated receptor gamma activity in esophageal carcinoma cells results in a drastic decrease of invasive properties. Cancer Sci. 2006;97(9):854–860.

    Article  CAS  PubMed  Google Scholar 

  14. Burton JD, Goldenberg DM, Blumenthal RD. Potential of peroxisome proliferator-activated receptor gamma antagonist compounds as therapeutic agents for a wide range of cancer types. PPAR Res. 2008;2008:494161.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Kim KR, Choi HN, Lee HJ, et al. A peroxisome proliferator-activated receptor gamma antagonist induces vimentin cleavage and inhibits invasion in high-grade hepatocellular carcinoma. Oncol Rep. 2007;18(4):825–832.

    CAS  PubMed  Google Scholar 

  16. Hall EJ, Giaccia AJ. Radiosensitivity and cell age in the mitotic cycle. In: Lippincott Williams and Wilkins, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2011:54–66.

  17. Tsao MS, Earp HS, Grisham JW. Gradation of carcinogen-induced capacity for anchorage-independent growth in cultured rat liver epithelial cells. Cancer Res. 1985;45(9):4428–4432.

    CAS  PubMed  Google Scholar 

  18. Landsverk KS, Lyng H, Stokke T. The response of malignant B lymphocytes to ionizing radiation: cell cycle arrest, apoptosis and protection against the cytotoxic effects of the mitotic inhibitor nocodazole. Radiat Res. 2004;162(4):405–415.

    Article  CAS  PubMed  Google Scholar 

  19. Pines J, Hunter T. Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B. Nature. 1990; 346(6286):760–763.

    Article  CAS  PubMed  Google Scholar 

  20. Innocente SA, Abrahamson JL, Cogswell JP, Lee JM. p53 regulates a G2 checkpoint through cyclin B1. Proc Natl Acad Sci U S A. 1999;96(5):2147–2152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Niméus-Malmström E, Koliadi A, Ahlin C, et al. Cyclin B1 is a prognostic proliferation marker with a high reproducibility in a population-based lymph node negative breast cancer cohort. Int J Cancer. 2010;127(4):961–967.

    PubMed  Google Scholar 

  22. Kosacka M, Korzeniewska A, Jankowska R. The evaluation of prognostic value of cyclin B1 expression in patients with resected non-small-cell lung cancer stage I-IIIA–preliminary report [in Polish]. Pol Merkur Lekarski. 2010;28(164):117–121.

    CAS  PubMed  Google Scholar 

  23. Weaver BA, Cleveland DW. Decoding the links between mitosis, cancer, and chemotherapy: The mitotic checkpoint, adaptation, and cell death. Cancer Cell. 2005;8(1):7–12.

    Article  CAS  PubMed  Google Scholar 

  24. Yamada HY, Gorbsky GJ. Spindle checkpoint function and cellular sensitivity to antimitotic drugs. Mol Cancer Ther. 2006;5(12): 2963–2969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Eriksson D, Joniani HM, Sheikholvaezin A, et al. Combined low dose radio- and radioimmunotherapy of experimental HeLa Hep 2 tumours. Eur J Nucl Med Mol Imaging. 2003;30(6):895–906.

    Article  CAS  PubMed  Google Scholar 

  26. Eriksson D, Löfroth PO, Johansson L, Riklund KA, Stigbrand T. Cell cycle disturbances and mitotic catastrophes in HeLa Hep2 cells following 2.5 to 10 Gy of ionizing radiation. Clin Cancer Res. 2007;13(18 pt 2):5501s-5508s.

    Article  CAS  PubMed  Google Scholar 

  27. Castedo M, Kroemer G. Mitotic catastrophe: a special case of apoptosis [in French]. J Soc Biol. 2004;198(2):97–103.

    Article  CAS  PubMed  Google Scholar 

  28. Erenpreisa J, Kalejs M, Ianzini F, et al. Segregation of genomes in polyploid tumour cells following mitotic catastrophe. Cell Biol Int. 2005;29(12):1005–1011.

    Article  CAS  PubMed  Google Scholar 

  29. Roninson IB, Broude EV, Chang BD. If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist Updat. 2001;4(5):303–313.

    Article  CAS  PubMed  Google Scholar 

  30. Rieder CL, Maiato H. Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Dev Cell. 2004;7(5):637–651.

    Article  CAS  PubMed  Google Scholar 

  31. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239–257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol. 2001;3(11):E255–E263.

    Article  CAS  PubMed  Google Scholar 

  33. Brenner C, Kroemer G. Apoptosis. Mitochondria–the death signal integrators. Science. 2000; 289(5482):1150–1151.

    Article  CAS  PubMed  Google Scholar 

  34. Ravagnan L, Roumier T, Kroemer G. Mitochondria, the killer organelles and their weapons. J Cell Physiol. 2002;192(2):131–137.

    Article  CAS  PubMed  Google Scholar 

  35. Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G. Cell death by mitotic catastrophe: a molecular definition. Oncogene. 2004;23(16):2825–2837.

    Article  CAS  PubMed  Google Scholar 

  36. Xiao Z, Chen Z, Gunasekera AH, et al. Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. J Biol Chem. 2003;278(24):21767–2173.

    Article  CAS  PubMed  Google Scholar 

  37. Ashwell S, Zabludoff S. DNA damage detection and repair pathways—recent advances with inhibitors of checkpoint kinases in cancer therapy. Clin Cancer Res. 2008;14(13):4032–4037.

    Article  CAS  PubMed  Google Scholar 

  38. Burton JD, Castillo ME, Goldenberg DM, Blumenthal RD. Peroxisome proliferator-activated receptor-gamma antagonists exhibit potent antiproliferative effects versus many hematopoietic and epithelial cancer cell lines. Anticancer Drugs. 2007;18(5):525–534.

    Article  CAS  PubMed  Google Scholar 

  39. Kim KY, Kim SS, Cheon HG. Differential anti-proliferative actions of peroxisome proliferator-activated receptor-gamma agonists in MCF-7 breast cancer cells. Biochem Pharmacol. 2006;72(5):530–540.

    Article  CAS  PubMed  Google Scholar 

  40. Tachibana K, Yamasaki D, Ishimoto K, Doi T. The role of PPARs in cancer. PPAR Res. 2008;2008:102737.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Lea MA, Sura M, Desbordes C. Inhibition of cell proliferation by potential peroxisome proliferator-activated receptor (PPAR) gamma agonists and antagonists. Anticancer Res. 2004;24(5A): 2765–2771.

    CAS  PubMed  Google Scholar 

  42. Zaytseva YY, Wallis NK, Southard RC, Kilgore MW. The PPARgamma antagonist T0070907 suppresses breast cancer cell proliferation and motility via both PPARgamma-dependent and -independent mechanisms. Anticancer Res. 2011;31(3):813–823.

    CAS  PubMed  Google Scholar 

  43. Kumala S, Niemiec P, Widel M, Hancock R, Rzeszowska-Wolny J. Apoptosis and clonogenic survival in three tumour cell lines exposed to gamma rays or chemical genotoxic agents. Cell Mol Biol Lett. 2003;8(3):655–665.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Chungbuk National University College of Medicine, 52 Naesudong-ro, Heungduk-gu, 361-763, Cheongju, Republic of Korea

    Zhengzhe An MS, Sridhar Muthusami PhD & Woo-Yoon Park MD, PhD

  2. Department of Environmental and Tropical Medicine, Konkuk University College of Medicine, Chungju, Republic of Korea

    Jae-Ran Yu MD, PhD

Authors
  1. Zhengzhe An MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sridhar Muthusami PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jae-Ran Yu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Woo-Yoon Park MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Woo-Yoon Park MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

An, Z., Muthusami, S., Yu, JR. et al. T0070907, a PPAR γ Inhibitor, Induced G2/M Arrest Enhances the Effect of Radiation in Human Cervical Cancer Cells Through Mitotic Catastrophe. Reprod. Sci. 21, 1352–1361 (2014). https://doi.org/10.1177/1933719114525265

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719114525265

Keywords

Search

Navigation