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Ursolic acid inhibits multiple cell survival pathways leading to suppression of growth of prostate cancer xenograft in nude mice

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Abstract

Activation of transcription factors nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) is frequently observed in prostate cancer and has been linked with tumor cell proliferation, invasion, metastasis, and angiogenesis. In this study, we investigated the effect of ursolic acid (UA) on NF-κB and STAT3 signaling pathways in both androgen-independent (DU145) and androgen-dependent (LNCaP) prostate cancer cell lines and also prospectively tested the hypothesis of NF-κB and STAT3 inhibition using a virtual predictive functional proteomics tumor pathway technology platform. We found that UA inhibited constitutive and TNF-α-induced activation of NF-κB in DU145 and LNCaP cells in a dose-dependent manner. The suppression was mediated through the inhibition of constitutive and TNF-α-induced IκB kinase (IKK) activation, phosphorylation of IκBα and p65 and NF-κB-dependent reporter activity. Furthermore, UA suppressed both constitutive and inducible STAT3 activation in prostate cancer cells concomitant with suppression of activation of upstream kinases (Src and JAK2) and STAT3-dependent reporter gene activity. UA also downregulated the expression of various NF-κB and STAT3 regulated gene products involved in proliferation, survival, and angiogenesis and induced apoptosis in both cells lines as evidenced by DNA fragmentation and annexin V staining. In vivo, UA (200 mg/kg b.w.) treated for 6 weeks inhibited the growth of DU145 cells in nude mice without any significant effect on body weight. Overall, our results from experimental and predictive studies suggest that UA mediates its anti-tumor effects through suppression of NF-κB and STAT3 pathways in prostate cancer.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96

    Article  PubMed  Google Scholar 

  2. Damber JE, Aus G (2008) Prostate cancer. Lancet 371:1710–1721

    Article  PubMed  Google Scholar 

  3. Vasto S, Carruba G, Candore G, Italiano E, Di Bona D, Caruso C (2008) Inflammation and prostate cancer. Future Oncol 4:637–645

    Article  PubMed  Google Scholar 

  4. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809

    Article  PubMed  CAS  Google Scholar 

  5. Grivennikov SI, Karin M (2010) Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 21:11–19

    Article  PubMed  CAS  Google Scholar 

  6. Liu J (1995) Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol 49:57–68

    Article  PubMed  CAS  Google Scholar 

  7. Kassi E, Papoutsi Z, Pratsinis H, Aligiannis N, Manoussakis M, Moutsatsou P (2007) Ursolic acid, a naturally occurring triterpenoid, demonstrates anticancer activity on human prostate cancer cells. J Cancer Res Clin Oncol 133:493–500

    Article  PubMed  CAS  Google Scholar 

  8. Pathak AK, Bhutani M, Nair AS, Ahn KS, Chakraborty A, Kadara H, Guha S, Sethi G, Aggarwal BB (2007) Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol Cancer Res 5:943–955

    Article  PubMed  CAS  Google Scholar 

  9. Manu KA, Kuttan G (2008) Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-kappaB mediated activation of bcl-2 in B16F-10 melanoma cells. Int Immunopharmacol 8:974–981

    Article  PubMed  CAS  Google Scholar 

  10. Kassi E, Sourlingas TG, Spiliotaki M, Papoutsi Z, Pratsinis H, Aligiannis N, Moutsatsou P (2009) Ursolic acid triggers apoptosis and Bcl-2 downregulation in MCF-7 breast cancer cells. Cancer Invest 27:723–733

    Article  PubMed  CAS  Google Scholar 

  11. Kiran MS, Viji RI, Sameer Kumar VB, Sudhakaran PR (2008) Modulation of angiogenic factors by ursolic acid. Biochem Biophys Res Commun 371:556–560

    Article  PubMed  CAS  Google Scholar 

  12. Zhang Y, Kong C, Zeng Y, Wang L, Li Z, Wang H, Xu C, Sun Y (2010) Ursolic acid induces PC-3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro. Mol Carcinog 49:374–385

    PubMed  CAS  Google Scholar 

  13. Li F, Sethi G (2010) Targeting transcription factor NF-kappaB to overcome chemoresistance and radioresistance in cancer therapy. Biochim Biophys Acta 1805:167–180

    PubMed  CAS  Google Scholar 

  14. Cirstea D, Hideshima T, Rodig S, Santo L, Pozzi S, Vallet S, Ikeda H, Perrone G, Gorgun G, Patel K, Desai N, Sportelli P, Kapoor S, Vali S, Mukherjee S, Munshi NC, Anderson KC, Raje N (2010) Dual inhibition of akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma. Mol Cancer Ther 9:963–975

    Article  PubMed  CAS  Google Scholar 

  15. Tan SM, Li F, Rajendran P, Kumar AP, Hui KM, Sethi G (2010) Identification of beta-escin as a novel inhibitor of signal transducer and activator of transcription 3/Janus-activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells. J Pharmacol Exp Ther 334:285–293

    Article  PubMed  CAS  Google Scholar 

  16. Rabi T, Shukla S, Gupta S (2008) Betulinic acid suppresses constitutive and TNFalpha-induced NF-kappaB activation and induces apoptosis in human prostate carcinoma PC-3 cells. Mol Carcinog 47:964–973

    Article  PubMed  CAS  Google Scholar 

  17. Renard P, Ernest I, Houbion A, Art M, Le Calvez H, Raes M, Remacle J (2001) Development of a sensitive multi-well colorimetric assay for active NFkappaB. Nucleic Acids Res 29:E21

    Article  PubMed  CAS  Google Scholar 

  18. Mukhopadhyay A, Bueso-Ramos C, Chatterjee D, Pantazis P, Aggarwal BB (2001) Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines. Oncogene 20:7597–7609

    Article  PubMed  CAS  Google Scholar 

  19. Li F, Fernandez PP, Rajendran P, Hui KM, Sethi G (2010) Diosgenin, a steroidal saponin, inhibits STAT3 signaling pathway leading to suppression of proliferation and chemosensitization of human hepatocellular carcinoma cells. Cancer Lett 292:197–207

    Article  PubMed  CAS  Google Scholar 

  20. Li F, Rajendran P, Sethi G (2010) Thymoquinone inhibits proliferation, induces apoptosis and chemosensitizes human multiple myeloma cells through suppression of signal transducer and activator of transcription 3 activation pathway. Br J Pharmacol 161:541–554

    Article  PubMed  CAS  Google Scholar 

  21. Mickey DD, Stone KR, Wunderli H, Mickey GH, Vollmer RT, Paulson DF (1977) Heterotransplantation of a human prostatic adenocarcinoma cell line in nude mice. Cancer Res 37:4049–4058

    PubMed  CAS  Google Scholar 

  22. Liao Q, Yang W, Jia Y, Chen X, Gao Q, Bi K (2005) LC–MS determination and pharmacokinetic studies of ursolic acid in rat plasma after administration of the traditional Chinese medicinal preparation Lu-Ying extract. Yakugaku Zasshi 125:509–515

    Article  PubMed  CAS  Google Scholar 

  23. Rajendran P, Ong TH, Chen L, Li F, Shanmugam M, Vali S, Abbasi T, Kapoor S, Sharma A, Kumar AP, Hui KM, Sethi G (2011) Suppression of signal transducer and activator of transcription 3 activation by butein inhibits growth of human hepatocellular carcinoma in vivo. Clin Cancer Res 17:1425–1439

    Article  PubMed  CAS  Google Scholar 

  24. Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260

    Article  PubMed  CAS  Google Scholar 

  25. Sethi G, Sung B, Aggarwal BB (2008) TNF: a master switch for inflammation to cancer. Front Biosci 13:5094–5107

    Article  PubMed  CAS  Google Scholar 

  26. Tanaka H, Fujita N, Tsuruo T (2005) 3-Phosphoinositide-dependent protein kinase-1-mediated IkappaB kinase beta (IkkB) phosphorylation activates NF-kappaB signaling. J Biol Chem 280:40965–40973

    Article  PubMed  CAS  Google Scholar 

  27. Gustin JA, Maehama T, Dixon JE, Donner DB (2001) The PTEN tumor suppressor protein inhibits tumor necrosis factor-induced nuclear factor kappa B activity. J Biol Chem 276:27740–27744

    Article  PubMed  CAS  Google Scholar 

  28. Sethi G, Tergaonkar V (2009) Potential pharmacological control of the NF-kappaB pathway. Trends Pharmacol Sci 30:313–321

    Article  PubMed  CAS  Google Scholar 

  29. Ahn KS, Sethi G, Aggarwal BB (2007) Nuclear factor-kappa B: from clone to clinic. Curr Mol Med 7:619–637

    Article  PubMed  CAS  Google Scholar 

  30. Shishodia S, Majumdar S, Banerjee S, Aggarwal BB (2003) Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res 63:4375–4383

    PubMed  CAS  Google Scholar 

  31. Sethi G, Ahn KS, Sandur SK, Lin X, Chaturvedi MM, Aggarwal BB (2006) Indirubin enhances tumor necrosis factor-induced apoptosis through modulation of nuclear factor-kappa B signaling pathway. J Biol Chem 281:23425–23435

    Article  PubMed  CAS  Google Scholar 

  32. Narayanan NK, Nargi D, Randolph C, Narayanan BA (2009) Liposome encapsulation of curcumin and resveratrol in combination reduces prostate cancer incidence in PTEN knockout mice. Int J Cancer 125:1–8

    Article  PubMed  CAS  Google Scholar 

  33. Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA, Cox CE, Falcone R, Fairclough R, Parsons S, Laudano A, Gazit A, Levitzki A, Kraker A, Jove R (2001) Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 20:2499–2513

    Article  PubMed  CAS  Google Scholar 

  34. Lee H, Herrmann A, Deng JH, Kujawski M, Niu G, Li Z, Forman S, Jove R, Pardoll DM, Yu H (2009) Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell 15:283–293

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from National Medical Research Council of Singapore (Grant R-184-000-168-275, Grant R-184-000-157-214) to GS. APK was supported by grants from the National Medical Research Council of Singapore (Grant R-713-000-124-213) and Cancer Science Institute of Singapore, Experimental Therapeutics I Program (Grant R-713-001-011-271). KMH was supported by grant from the National Medical Research Council of Singapore, Biomedical Research Council of Singapore, and the Singapore Millennium Foundation.

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No potential conflict of interest is declared.

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Correspondence to Gautam Sethi.

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Shanmugam, M.K., Rajendran, P., Li, F. et al. Ursolic acid inhibits multiple cell survival pathways leading to suppression of growth of prostate cancer xenograft in nude mice. J Mol Med 89, 713–727 (2011). https://doi.org/10.1007/s00109-011-0746-2

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  • DOI: https://doi.org/10.1007/s00109-011-0746-2

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