, Volume 11, Issue 11, pp 1969–1975 | Cite as

P38 MAPK protects against TNF-α-provoked apoptosis in LNCaP prostatic cancer cells

  • M. Ricote
  • I. García-Tuñón
  • B. Fraile
  • C. Fernández
  • P. Aller
  • R. Paniagua
  • M. Royuela


Purpose: One of the most relevant aspects in cell death regulation is the signalling of apoptosis by the serine/threonine kinases MAPKs. The aim of this study was to investigate the effects of TNF-α stimulation on MAPK activation, and the pro- or anti-apoptotic role of these kinases in LNCaP and PC3 cells. Material and methods: Treatments were carried out using several TNF-α concentrations, as well as specific pharmacological inhibitors of MAPKs. Apoptosis rates were evaluated by DAPI staining and flow cytometry. MAPK phosphorylation/activation was measured by Western blot. Results: TNF-α induced apoptosis in a dose-dependent manner in LNCaP but not in PC3 cells. The MAPK inhibitors revealed that the apoptotic rate in LNCaP cells increased significantly following p38 inhibition. The kinase inhibitors failed to cause changes in apoptosis in PC3 cells. Conclusions: The potentiation of apoptosis by p38 inhibition points to this kinase as a possible target for the treatment of androgen-dependent prostatic cancer.


Apoptosis Protate Cancer LNCap PC3 P38 TNF 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Szlosarek PW, Balkwill FR (2003) Tumour necrosis factor alpha: a potential target for the therapy of solid tumours. Oncology 4:565–573PubMedGoogle Scholar
  2. 2.
    Lejeune FJ, Ruegg C, Lienard D (1998) Clinical applications of TNF-alpha in cancer. Curr Opinion Immunol 10:573–580CrossRefGoogle Scholar
  3. 3.
    Kollias G, Douni E, Kassiotis G, Kontoyiannis D (1999) On the role of tumor necrosis factor and receptors in models of multiorgan failure, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Immunol Rev 169:175–194PubMedCrossRefGoogle Scholar
  4. 4.
    Balkwill F (2002) Tumor necrosis factor or tumor promoting factor? Cytokine Growth Factor Rev 13:135–141PubMedCrossRefGoogle Scholar
  5. 5.
    Cross TG, Scheel-Toellner D, Henriquez NV, Deacon E, Salmon M, Lord JM (2002) Serine/threonine protein kinases and apoptosis. Exp Cell Res 256:34–41CrossRefGoogle Scholar
  6. 6.
    Ichijo H, Nishida E, Irie K, Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y (1997) Induction of apoptosis by ASK-1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275:90–94PubMedCrossRefGoogle Scholar
  7. 7.
    Lüschen S, Scherer, Ussat S, Ungenfroren H, Adam-Klages S (2004) Inhibition of p38 mitogen-activated protein kinase reduces TNF-induced activation of NF-kB, elicits caspase activity, and enhances cytotoxicity. Exp Cell Res 293:196–206PubMedCrossRefGoogle Scholar
  8. 8.
    Beg AA, Baltimore D (1996) An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274:782–784PubMedCrossRefGoogle Scholar
  9. 9.
    Kim JA, Kim DK, Kang OH, Choi YA, Park HJ, Choi SC, Kim TH, Yun KJ, Nah YH, Lee YM (2005) Inhibitory effect of luteolin on TNF-alpha-induced IL-8 production in human colon epithelial cells. Immunopharmacol 5:209–217CrossRefGoogle Scholar
  10. 10.
    De Miguel MP, Royuela M, Bethencourt FR, Santamaria L, Fraile B, Paniagua R (2000) Immunoexpression of tumour necrosis factor-alpha and its receptors 1 and 2 correlates with proliferation/apoptosis equilibrium in normal, hyperplasic and carcinomatous human prostate. Cytokine 12:535–538PubMedCrossRefGoogle Scholar
  11. 11.
    Royuela M, Arenas MI, Bethencourt FR, Sanchez Chapado M, Fraile B, Paniagua R (2002) Regulation of Proliferation/Apoptosis equilibrium by mitogen-activated protein kinases in Normal, Hyperplastic, and carcinomatous human prostate. Human Pahthol 33:299–306CrossRefGoogle Scholar
  12. 12.
    Ricote M, Royuela M, Garcia-Tunon I, Bethencourt FR, Paniagua R, Fraile B (2003) Pro-apoptotic tumor necrosis factor-alpha transduction pathway in normal prostate, benign prostatic hyperplasia and prostatic carcinoma. J Urol 170:787–790PubMedCrossRefGoogle Scholar
  13. 13.
    Kimura K, Bowen C, Spiegel S, Gelmann EP (1999) Tumor necrosis factor-alpha sensitizes prostate cancer cells to gamma-irradiation-induced apoptosis. Cancer Res 59:1606–1614PubMedGoogle Scholar
  14. 14.
    Foa R, Massaia M, Cardona S, Tos AG, Bianchi A, Attisano C, Guarini A, di Celle PF, Fierro MT (1990) Production of tumor necrosis factor-alpha by B-cell chronic lymphocytic leukemia cells: a possible regulatory role of TNF in the progression of the disease. Blood 76:393–400PubMedGoogle Scholar
  15. 15.
    Sintich SM, Steinberg J, Kozlowski JM, Lee C, Pruden S, Sayeed S, Sensibar JA (1999) Cytotoxic sensitivity to tumor necrosis factor-alpha in PC3 and LNCaP prostatic cancer cells is regulated by extracellular levels of SGP-2 (clusterin). Prostate 39:87–93PubMedCrossRefGoogle Scholar
  16. 16.
    Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N, Holdsworth H, Turner L, Rollins B, Pasparakis M, Kollias G, Balkwill F (1999) Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 5:828–831PubMedCrossRefGoogle Scholar
  17. 17.
    Zhang S, Han J, Sells MA, Chernorff J, Knaus UG, Ulevitch RJ, Bokoch GM (1995) Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator PAK1. J Biol Chem 270:23934–23936PubMedCrossRefGoogle Scholar
  18. 18.
    Ogasawara T, Yasuyama M Kawauchi K (2003) Constitutive activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in B-cell lymphoproliferative disorders. Int J Hematol 77:364–370PubMedCrossRefGoogle Scholar
  19. 19.
    Vaarala MH, Porvari K, Kyllonen A, Vihko P (2000) Differentially expressed genes in two LNCaP prostate cancer cell lines reflecting changes during prostate cancer progression. Lab Invest 80:1259–1268PubMedCrossRefGoogle Scholar
  20. 20.
    Aihara M, Scardino PT, Truong LD, Wheeler TM, Goad JR, Yang G, Thompson TC (1995) The frequency of apoptosis correlates with the prognosis of Gleason Grade 3 adenocarcinoma of the prostate. Cancer 75:522–529PubMedCrossRefGoogle Scholar
  21. 21.
    Kanabbe C, Kellner U, Schmahl M, Voigt KD (1991) Growth factors in hyman prostate cancer cells: implications for an improved treatment of prostate canc. J Steroid Biochem Mol Biol 40:185–192CrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • M. Ricote
    • 1
  • I. García-Tuñón
    • 1
  • B. Fraile
    • 1
  • C. Fernández
    • 2
  • P. Aller
    • 2
  • R. Paniagua
    • 1
  • M. Royuela
    • 1
  1. 1.Departmento de Biología Celular y GenéticaUniversidad de AlcaláMadridSpain
  2. 2.Centro de Investigaciones BiológicasConsejo Superior de Investigaciones CientíficasMadridSpain

Personalised recommendations