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Ubiquitination of p53 is Involved in Troglitazone Induced Apoptosis in Cervical Cancer Cells

  • Chen, Hui-Min (Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College) ;
  • Zhang, Ding-Guo (Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College) ;
  • Wu, Jin-Xiz (Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College) ;
  • Pei, Dong-Sheng (Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College) ;
  • Zheng, Jun-Nian (Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College)
  • Published : 2014.03.01

Abstract

Peroxisome proliferator-activated receptor gamma (PPAR-${\gamma}$), a ligand-dependent nuclear transcription factor, has been found to widely exist in tumor tissues and plays an important role in affecting tumor cell growth. In this study, we investigated the effect of PPAR-${\gamma}$ on aspects of the cervical cancer malignant phenotype, such as cell proliferation and apoptosis. Cell growth assay, Western blotting, Annexin V and flow cytometry analysis consistently showed that treatment with troglitazone (TGZ, a PPAR-${\gamma}$ agonist) led to dose-dependent inhibition of cervical cancer cell growth through apoptosis, whereas T0070907 (another PPAR-${\gamma}$ antagonist) had no effect on Hela cell proliferation and apoptosis. Furthermore, we also detected the protein expression of p53, p21 and Mdm2 to explain the underlying mechanism of PPAR-${\gamma}$ on cellular apoptosis. Our work, finally, demonstrated the existence of the TGZ-PPAR-${\gamma}$-p53 signaling pathway to be a critical regulator of cell apoptosis. These results suggested that PPAR-${\gamma}$ may be a potential therapeutic target for cervical cancer.

Keywords

References

  1. Canbay E, Kurnaz O, Canbay B, et al (2012). PPAR-gamma Pro12Ala polymorphism and gastric cancer risk in a Turkish population. Asian Pac J Cancer Prev, 13, 5875-8. https://doi.org/10.7314/APJCP.2012.13.11.5875
  2. Cheon CW, Kim DH, Kim DH, Cho YH, Kim JH (2009). Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol, 15, 310-20. https://doi.org/10.3748/wjg.15.310
  3. Choi HH, Gully C, Su CH, et al (2011). COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3sigma. Oncogene, 30, 4791-801. https://doi.org/10.1038/onc.2011.192
  4. Dong YW, Wang XP, Wu K (2009). Suppression of pancreatic carcinoma growth by activating peroxisome proliferatoractivated receptor gamma involves angiogenesis inhibition. World J Gastroenterol, 15, 441-8. https://doi.org/10.3748/wjg.15.441
  5. Han S, Roman J (2006). Rosiglitazone suppresses human lung carcinoma cell growth through PPARgamma-dependent and PPARgamma-independent signal pathways. Mol Cancer Ther, 5, 430-7. https://doi.org/10.1158/1535-7163.MCT-05-0347
  6. Hasan TN, B LG, Shafi G, Al-Hazzani AA, Alshatwi AA (2011). Anti-proliferative effects of organic extracts from root bark of Juglans Regia L. (RBJR) on MDA-MB-231 human breast cancer cells: role of Bcl-2/Bax, caspases and Tp53. Asian Pac J Cancer Prev, 12, 525-30.
  7. Hassan ZK, Elamin MH, Omer SA, et al (2013). Oleuropein induces apoptosis via the p53 pathway in breast cancer cells. Asian Pac J Cancer Prev, 14, 6739-42. https://doi.org/10.7314/APJCP.2013.14.11.6739
  8. Jung TI, Baek WK, Suh SI, et al (2005). Down regulation of peroxisome proliferator-activated receptor gamma in human cervical carcinoma. Gynecol Oncol, 97, 365-73. https://doi.org/10.1016/j.ygyno.2005.01.019
  9. Kawa S, Nikaido T, Unno H, et al (2002). Growth inhibition and differentiation of pancreatic cancer cell lines by PPAR gamma ligand troglitazone. Pancreas, 24, 1-7. https://doi.org/10.1097/00006676-200201000-00001
  10. Kim S, Lee JJ, Heo DS (2011). PPARgamma ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells. Biochem Bioph Res Com, 406, 389-95. https://doi.org/10.1016/j.bbrc.2011.02.052
  11. Li M, Lee TW, Mok TS, et al (2005). Activation of peroxisome proliferator-activated receptor-gamma by troglitazone (TGZ) inhibits human lung cell growth. J Cell Biochem, 96, 760-74. https://doi.org/10.1002/jcb.20474
  12. Li Y, Zhang S, Geng JX, and Hu XY (2013). Curcumin inhibits human non-small cell lung cancer A549 cell proliferation through regulation of Bcl-2/Bax and cytochrome C. Asian Pac J Cancer Prev, 14, 4599-602. https://doi.org/10.7314/APJCP.2013.14.8.4599
  13. Liu JJ, Huang RW, Lin DJ, et al (2005). Expression of survivin and bax/bcl-2 in peroxisome proliferator activated receptorgamma ligands induces apoptosis on human myeloid leukemia cells in vitro. Ann Oncol, 16, 455-9. https://doi.org/10.1093/annonc/mdi077
  14. Matsuyama M, and Yoshimura R (2009). A novel approach to anticancer therapies: peroxisome proliferator activatorreceptor-gamma as a new target therapy in the treatment of human urological cancer. Endocr Metab Immune Disord Drug Targets, 9, 76-83. https://doi.org/10.2174/187153009787582432
  15. Nagamine M, Okumura T, Tanno S, et al (2003). PPAR gamma ligand-induced apoptosis through a p53-dependent mechanism in human gastric cancer cells. Cancer Sci, 94, 338-43. https://doi.org/10.1111/j.1349-7006.2003.tb01443.x
  16. Nagata D, Yoshihiro H, Nakanishi M, et al (2008). Peroxisome proliferator-activated receptor-gamma and growth inhibition by its ligands in prostate cancer. Cancer Detect Prev, 32, 259-66. https://doi.org/10.1016/j.cdp.2008.05.008
  17. Nam DH, Ramachandran S, Song DK, et al (2007). Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR gamma ligand ciglitizone. Mol Hum Reprod, 13, 829-36. https://doi.org/10.1093/molehr/gam071
  18. Ohtani S, Kagawa S, Tango Y, et al (2004). Quantitative analysis of p53-targeted gene expression and visualization of p53 transcriptional activity following intratumoral administration of adenoviral p53 in vivo. Mol Cancer Ther, 3, 93-100.
  19. Okamoto K, Taya Y, Nakagama H (2009). Mdmx enhances p53 ubiquitination by altering the substrate preference of the Mdm2 ubiquitin ligase. Febs Lett, 583, 2710-4. https://doi.org/10.1016/j.febslet.2009.07.021
  20. Park JW, Zarnegar R, Kanauchi H, et al (2005). Troglitazone, the peroxisome proliferator-activated receptor-gamma agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines. Thyroid, 15, 222-31. https://doi.org/10.1089/thy.2005.15.222
  21. Pei DS, Yang ZX, Zhang BF, et al (2012). Enhanced apoptosis-inducing function of MDA-7/IL-24 RGD mutant via the increased adhesion to tumor cells. J Interferon Cytokine Res, 32, 66-73. https://doi.org/10.1089/jir.2011.0040
  22. Tian H, Wang J, Zhang B, et al (2012). MDA-7/IL-24 induces Bcl-2 denitrosylation and ubiquitin-degradation involved in cancer cell apoptosis. Plos One, 7, e37200. https://doi.org/10.1371/journal.pone.0037200
  23. Ueno T, Teraoka N, Takasu S, et al (2012). Suppressive effect of pioglitazone, a PPAR gamma ligand, on azoxymethaneinduced colon aberrant crypt foci in KK-Ay mice. Asian Pac J Cancer P, 13, 4067-73. https://doi.org/10.7314/APJCP.2012.13.8.4067
  24. Wu JS, Lin TN, Wu KK (2009). Rosiglitazone and PPAR-gamma overexpression protect mitochondrial membrane potential and prevent apoptosis by upregulating anti-apoptotic Bcl-2 family proteins. J Cell Physiol, 220, 58-71. https://doi.org/10.1002/jcp.21730
  25. Yoshimura R, Matsuyama M, Segawa Y, et al (2003). Expression of peroxisome proliferator-activated receptors (PPARs) in human urinary bladder carcinoma and growth inhibition by its agonists. Int J Cancer, 104, 597-602. https://doi.org/10.1002/ijc.10980
  26. Yu J, Qiao L, Zimmermann L, et al (2006). Troglitazone inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo. Hepatology, 43, 134-43. https://doi.org/10.1002/hep.20994
  27. Zaytseva YY, Wallis NK, Southard RC, Kilgore MW (2011). The PPARgamma antagonist T0070907 suppresses breast cancer cell proliferation and motility via both PPARgammadependent and -independent mechanisms. Anticancer Res, 31, 813-23.
  28. Zhou YM, Wen YH, Kang XY, et al (2008). Troglitazone, a peroxisome proliferator-activated receptor gamma ligand, induces growth inhibition and apoptosis of HepG2 human liver cancer cells. World J Gastroenterol, 14, 2168-73. https://doi.org/10.3748/wjg.14.2168

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