Molecular Medicine

, Volume 14, Issue 7–8, pp 403–411 | Cite as

Rosiglitazone Attenuates Insulin-Like Growth Factor 1 Receptor Survival Signaling in PC-3 Cells

  • Efstathia Papageorgiou
  • Nea Pitulis
  • Menelaos Manoussakis
  • Peter Lembessis
  • Michael Koutsilieris
Research Article


PPARγ, a member of the peroxisome proliferator-activated receptor family, is overexpressed in prostate cancer. Natural and synthetic ligands of PPARγ via genomic and nongenomic actions promote cell cycle arrest and apoptosis of several prostate cancer cells, in vitro. Insulin-like growth factor 1 (IGF-1) inhibits the adriamycin-induced apoptosis of PC-3 human prostate cancer cells. Therefore, we have analyzed the ability of two PPARγ ligands,15dPGJ2 and rosiglitazone, a natural and a synthetic PPARγ ligand, respectively, to increase the adriamycin-induced cytotoxicity of PC-3 cells and to suppress the IGF-1 survival effect on adriamycin-induced apoptosis of PC-3 cells. Our data revealed that both the PPARγ ligands increased the adriamycin-induced cytostasis of PC-3 cells, however, only rosiglitazone added to the adriamycin-induced apoptosis of PC-3 cells. In addition, rosiglitazone attenuated the type I IGF receptor (IGF-1R) survival signaling on adriamycin-induced apoptosis of PC-3 cells via its nongenomic action on ERK1/2 and AKT phosphorylation. Because the IGF-1R signaling is probably the most important host tissue (bone) metastasis microenvironment-related survival signaling for prostate cancer cells, we conclude that rosiglitazone effects on IGF-1R-mediated activation of ERK1/2 and AKT could have clinical implications for the management of androgen ablation-refractory and chemotherapy-resistant advanced prostate cancer with bone metastasis.



The authors would like to thank Prof. Athanasios Papavassiliou for comments and suggestions regarding the context of this manuscript.


  1. 1.
    Labrie F et al. (1993) Downstaging of localized prostate cancer by neoadjuvant therapy with flutamide and lupron: the first controlled and randomized trial. Clin. Invest. Med. 16:499–509.PubMedGoogle Scholar
  2. 2.
    Labrie F et al. (1993) Optimized strategy for detection of early stage, curable prostate cancer: role of prescreening with prostate-specific antigen. Clin. Invest. Med. 16:425–39.PubMedGoogle Scholar
  3. 3.
    Koutsilieris M, Tolis G. (1985) Long-term follow-up of patients with advanced prostatic carcinoma treated with either buserelin (HOE 766) or orchiectomy: classification of variables associated with disease outcome. Prostate. 7:31–9.CrossRefGoogle Scholar
  4. 4.
    Tolis G et al. (1983) Suppression of testicular steroidogenesis by the GnRH agonistic analogue Buserelin (HOE-766) in patients with prostatic cancer: studies in relation to dose and route of administration. J. Steroid Biochem. 19:995–8.CrossRefGoogle Scholar
  5. 5.
    Koutsilieris M et al. (1986) Objective response and disease outcome in 59 patients with stage D2 prostatic cancer treated with either Buserelin or orchiectomy. Disease aggressivity and its association with response and outcome. Urology. 27:221–8.CrossRefGoogle Scholar
  6. 6.
    Koutsilieris M, Rabbani SA, Bennett HP, Goltzman D. (1987) Characteristics of prostate-derived growth factors for cells of the osteoblast phenotype. J. Clin. Invest. 80:941–6.CrossRefGoogle Scholar
  7. 7.
    Koutsilieris M, Rabbani SA, Goltzman D. (1987) Effects of human prostatic mitogens on rat bone cells and fibroblasts. J. Endocrinol. 115:447–54.CrossRefGoogle Scholar
  8. 8.
    Polychronakos C, Janthly U, Lehoux JG, Koutsilieris M. (1991) Mitogenic effects of insulin and insulin-like growth factors on PA-III rat prostate adenocarcinoma cells: characterization of the receptors involved. Prostate. 19:313–21.CrossRefGoogle Scholar
  9. 9.
    Koutsilieris M, Polychronakos C. (1992) Proteinolytic activity against IGF-binding proteins involved in the paracrine interactions between prostate adenocarcinoma cells and osteoblasts. Anticancer Res. 12:905–10.PubMedGoogle Scholar
  10. 10.
    Koutsilieris M. (1995) Skeletal metastases in advanced prostate cancer: cell biology and therapy. Crit. Rev. Oncol. Hematol. 18:51–64.CrossRefGoogle Scholar
  11. 11.
    Reyes-Moreno C, Sourla A, Choki I, Doillon C, Koutsilieris M. (1998) Osteoblast-derived survival factors protect PC-3 human prostate cancer cells from adriamycin apoptosis. Urology. 52:341–7.CrossRefGoogle Scholar
  12. 12.
    Koutsilieris M, Mitsiades C, Sourla A. (2000) Insulin-like growth factor I and urokinase-type plasminogen activator bioregulation system as a survival mechanism of prostate cancer cells in osteoblastic metastases: development of anti-survival factor therapy for hormone-refractory prostate cancer. Mol. Med. 6:251–67.CrossRefGoogle Scholar
  13. 13.
    Mitsiades CS, Koutsilieris M. (2001) Molecular biology and cellular physiology of refractoriness to androgen ablation therapy in advanced prostate cancer. Expert Opin. Investig. Drugs. 10:1099–15.CrossRefGoogle Scholar
  14. 14.
    Karamanolakis D et al. (2002) Molecular evidence-based use of bone resorption-targeted therapy in prostate cancer patients at high risk for bone involvement. Mol. Med. 8:667–75.CrossRefGoogle Scholar
  15. 15.
    Bogdanos J et al. (2003) Endocrine/paracrine/autocrine survival factor activity of bone microenvironment participates in the development of androgen ablation and chemotherapy refractoriness of prostate cancer metastasis in skeleton. Endocr. Relat. Cancer. 10:279–89.CrossRefGoogle Scholar
  16. 16.
    Tenta R et al. (2004) Bone microenvironmentrelated growth factors modulate differentially the anticancer actions of zoledronic acid and doxorubicin on PC-3 prostate cancer cells. Prostate. 59:120–31.CrossRefGoogle Scholar
  17. 17.
    Mitsiades CS, Mitsiades N, Koutsilieris M. (2004) The Akt pathway: molecular targets for anti-cancer drug development. Curr. Cancer Drug Targets. 4:235–56.CrossRefGoogle Scholar
  18. 18.
    Tenta R, Sourla A, Lembessis P, Luu-The V, Koutsilieris M. (2005) Bone microenvironmentrelated growth factors, zoledronic acid and dexamethasone differentially modulate PTHrP expression in PC-3 prostate cancer cells. Horm. Metab. Res. 37:593–601.CrossRefGoogle Scholar
  19. 19.
    Tenta R et al. (2007) Microarray analysis of survival pathways in human PC-3 prostate cancer cells. Cancer Genomics Proteomics. 4:309–18.PubMedGoogle Scholar
  20. 20.
    Grommes C, Landreth GE, Heneka MT. (2004) Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. Lancet Oncol. 5:419–29.CrossRefGoogle Scholar
  21. 21.
    Lennon AM, Ramauge M, Dessouroux A, Pierre M. (2002) MAP kinase cascades are activated in astrocytes and preadipocytes by 15-deoxy-Delta(12–14)-prostaglandin J(2) and the thiazolidinedione ciglitazone through peroxisome proliferator activator receptor gamma-independent mechanisms involving reactive oxygenated species. J. Biol. Chem. 277:29681–5.CrossRefGoogle Scholar
  22. 22.
    Gardner OS, Dewar BJ, Earp HS, Samet JM, Graves LM. (2003) Dependence of peroxisome proliferator-activated receptor ligand-induced mitogen-activated protein kinase signaling on epidermal growth factor receptor transactivation. J. Biol. Chem. 278:46261–9.CrossRefGoogle Scholar
  23. 23.
    Mueller E et al. (2000) Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc. Natl. Acad. Sci. U. S. A. 97:10990–5.CrossRefGoogle Scholar
  24. 24.
    Papageorgiou E, Pitulis N, Msaouel P, Lembessis P, Koutsilieris M. (2007) The non-genomic crosstalk between PPAR-gamma ligands and ERK1/2 in cancer cell lines. Expert Opin. Ther. Targets. 11: 1071–85.CrossRefGoogle Scholar
  25. 25.
    Hisatake JI et al. (2000) Down-regulation of prostate-specific antigen expression by ligands for peroxisome proliferator-activated receptor gamma in human prostate cancer. Cancer Res. 60:5494–8.PubMedGoogle Scholar
  26. 26.
    Kubota T et al. (1998) Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res. 58:3344–52.PubMedGoogle Scholar
  27. 27.
    Butler R, Mitchell SH, Tindall DJ, Young CY. (2000) Nonapoptotic cell death associated with S-phase arrest of prostate cancer cells via the peroxisome proliferator-activated receptor gamma ligand, 15-deoxy-delta12,14-prostaglandin J2. Cell Growth Differ. 11:49–61.PubMedGoogle Scholar
  28. 28.
    Koutsilieris M, Tzanela M, Dimopoulos T. (1999) Novel concept of antisurvival factor (ASF) therapy produces an objective clinical response in four patients with hormone-refractory prostate cancer: case report. Prostate. 38:313–6.CrossRefGoogle Scholar
  29. 29.
    Koutsilieris M et al. (2001) Acombination therapy of dexamethasone and somatostatin analog reintroduces objective clinical responses to LHRH analog in androgen ablation-refractory prostate cancer patients. J. Clin. Endocrinol. Metab. 86:5729–36.CrossRefGoogle Scholar
  30. 30.
    Koutsilieris M et al. (2002) Combination of dexamethasone and a somatostatin analogue in the treatment of advanced prostate cancer. Expert Opin. Investig. Drugs. 11:283–93.CrossRefGoogle Scholar
  31. 31.
    Tenta R, Sotiriou E, Pitulis N, Thyphronitis G, Koutsilieris M. (2005) Prostate cancer cell survival pathways activated by bone metastasis microenvironment. J. Musculoskelet. Neuronal. Interact. 5:135–44.PubMedGoogle Scholar
  32. 32.
    Kim YH et al. (2008) Rosiglitazone promotes tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP. Free Radic. Biol. Med. 44:1055–68.CrossRefGoogle Scholar
  33. 33.
    Shiau CW et al. (2005) Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPARgamma. Cancer Res. 65:1561–9.CrossRefGoogle Scholar
  34. 34.
    Laidler P, Dulinska J, Mrozicki S. (2007) Does the inhibition of c-myc expression mediate the antitumor activity of PPAR’s ligands in prostate cancer cell lines? Arch. Biochem. Biophys. 462:1–12.CrossRefGoogle Scholar
  35. 35.
    Girnun GD et al. (2007) Synergy between PPARgamma ligands and platinum-based drugs in cancer. Cancer Cell. 11:395–406.CrossRefGoogle Scholar
  36. 36.
    Patel C, Wyne KL, McGuire DK. (2005) Thiazolidinediones, peripheral oedema and congestive heart failure: what is the evidence? Diab. Vasc. Dis. Res. 2:61–6.CrossRefGoogle Scholar
  37. 37.
    Burstein HJ et al. (2003) Use of the peroxisome proliferator-activated receptor (PPAR) gamma ligand troglitazone as treatment for refractory breast cancer: a phase II study. Breast Cancer Res. Treat. 79:391–7.CrossRefGoogle Scholar
  38. 38.
    Hsi LC, Wilson LC, Eling TE. (2002) Opposing effects of 15-lipoxygenase-1 and -2 metabolites on MAPK signaling in prostate. Alteration in peroxisome proliferator-activated receptor gamma. J. Biol. Chem. 277:40549–56.CrossRefGoogle Scholar
  39. 39.
    Knuefermann C et al. (2003) HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene. 22:3205–12.CrossRefGoogle Scholar
  40. 40.
    Fresno Vara JA et al. (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat. Rev. 30:193–204.CrossRefGoogle Scholar
  41. 41.
    Koutsilieris M et al. (2006) Combination therapy using LHRH and somatostatin analogues plus dexamethasone in androgen ablation refractory prostate cancer patients with bone involvement: a bench to bedside approach. Expert Opin. Investig. Drugs. 15:795–804.CrossRefGoogle Scholar
  42. 42.
    Koutsilieris M et al. (2007) Combination of somatostatin analogues and dexamethasone (anti-survival-factor concept) with luteinizing hormone-releasing hormone in androgen ablation-refractory prostate cancer with bone metastasis. BJU Int. 100 Suppl 2:60–2.CrossRefGoogle Scholar
  43. 43.
    Revelos K et al. (2007) Correlation of androgen receptor status, neuroendocrine differentiation and angiogenesis with time-to-biochemical failure after radical prostatectomy in clinically localized prostate cancer. Anticancer Res. 27:3651–60.PubMedGoogle Scholar
  44. 44.
    Koutsilieris M, Laroche B, Thabet M, Fradet Y. (1990) The assessment of disease aggressivity in stage D2 prostate cancer patients (review). Anticancer Res. 10:333–6.PubMedGoogle Scholar
  45. 45.
    Koutsilieris M et al. (1993) Urokinase-type plasminogen activator: a paracrine factor regulating the bioavailability of IGFs in PA-III cell-induced osteoblastic metastases. Anticancer Res. 13:481–6.PubMedGoogle Scholar
  46. 46.
    Dupont A, Gomez JL, Cusan L, Koutsilieris M, Labrie F. (1993) Response to flutamide withdrawal in advanced prostate cancer in progression under combination therapy. J. Urol. 150:908–13.CrossRefGoogle Scholar
  47. 47.
    Koutsilieris M et al. (1994) Stratification of stage D2 prostate cancer patients by a disease aggressiveness score and its use in evaluating disease response and outcome to combination hormonal treatment (GnRH-A plus flutamide). Anticancer Res. 14:627–34.PubMedGoogle Scholar
  48. 48.
    Behrakis P, Koutsilieris M. (1997) Pulmonary metastases in metastatic prostate cancer: host tissue-tumor cell interactions and response to hormone therapy. Anticancer Res. 17:1517–8.PubMedGoogle Scholar
  49. 49.
    Koutsilieris M, Sourla A, Pelletier G, Doillon CJ. (1994) Three-dimensional type I collagen gel system for the study of osteoblastic metastases produced by metastatic prostate cancer. J. Bone Miner Res. 9:1823–32.CrossRefGoogle Scholar
  50. 50.
    Koutsilieris M et al. (2004) Combination of somatostatin analog, dexamethasone, and standard androgen ablation therapy in stage D3 prostate cancer patients with bone metastases. Cïin. Cancer Res. 10:4398–405.CrossRefGoogle Scholar
  51. 51.
    Mitsiades CS. (2006) Randomized controlled clinical trial of a combination of somatostatin analog and dexamethasone plus zoledronate vs. zoledronate in patients with androgen ablationrefractory prostate cancer. Anticancer Res. 26:3693–700.PubMedGoogle Scholar
  52. 52.
    Tsigkos S, Koutsilieris M, Papapetropoulos A. (2003) Angiopoietins in angiogenesis and beyond. Expert Opin. Investig. Drugs. 12:933–41.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Efstathia Papageorgiou
    • 1
  • Nea Pitulis
    • 1
  • Menelaos Manoussakis
    • 2
  • Peter Lembessis
    • 1
  • Michael Koutsilieris
    • 1
  1. 1.Department of Experimental Physiology, Medical SchoolNational and Kapodistrian University of AthensAthensGreece
  2. 2.Department of Pathophysiology, Medical SchoolNational and Kapodistrian University of Athens, GoudiAthensGreece

Personalised recommendations