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Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-κB activation and endothelial cell survival

Oncogene volume 26, pages 5722–5732 (2007)Cite this article

Abstract

Tumor necrosis factor (TNF) is a pro-inflammatory cytokine exerting pleiotropic effects on endothelial cells. Depending on the vascular context it can induce endothelial cell activation and survival or death. The microenvironmental cues determining whether endothelial cells will survive or die, however, have remained elusive. Here we report that integrin ligation acts permissive for TNF-induced protein kinase B (PKB/Akt) but not nuclear factor (NF)-κB activation. Concomitant activation of PKB/Akt and NF-κB is essential for the survival of endothelial cells exposed to TNF. Active PKB/Akt strengthens integrin-dependent endothelial cell adhesion, whereas disruption of actin stress fibers abolishes the protective effect of PKB/Akt. Integrin-mediated adhesion also represses TNF-induced JNK activation, but JNK activity is not required for cell death. The αVβ3/αVβ5 integrin inhibitor EMD121974 sensitizes endothelial cells to TNF-dependent cytotoxicity and active PKB/Akt attenuates this effect. Interferon γ synergistically enhanced TNF-induced endothelial cell death in all conditions tested. Taken together, these observations reveal a novel permissive role for integrins in TNF-induced PKB/Akt activation and prevention of TNF-induced death distinct of NF-κB, and implicate the actin cytoskeleton in PKB/Akt-mediated cell survival. The sensitizing effect of EMD121974 on TNF cytotoxicity may open new perspectives to the therapeutic use of TNF as anticancer agent.

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References

  • Agrawal S, Agarwal ML, Chatterjee-Kishore M, Stark GR, Chisolm GM . (2002). Stat1-dependent, p53-independent expression of p21(waf1) modulates oxysterol-induced apoptosis. Mol Cell Biol 22: 1981–1992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alghisi GC, Ruegg C . (2006). Vascular integrins in tumor angiogenesis: mediators and therapeutic targets. Endothelium 13: 113–135.

    Article  CAS  PubMed  Google Scholar 

  • Baker SJ, Reddy EP . (1998). Modulation of life and death by the TNF receptor superfamily. Oncogene 17: 3261–3270.

    Article  PubMed  Google Scholar 

  • Balkwill FR, Ward BG, Moodie E, Fiers W . (1987). Therapeutic potential of tumor necrosis factor-alpha and gamma-interferon in experimental human ovarian cancer. Cancer Res 47: 4755–4758.

    CAS  PubMed  Google Scholar 

  • Battle TE, Frank DA . (2002). The role of STATs in apoptosis. Curr Mol Med 2: 381–392.

    Article  CAS  PubMed  Google Scholar 

  • Beg AA, Baltimore D . (1996). An essential role for NF-kappa-B in preventing TNF-alpha-induced cell death. Science 274: 782–784.

    Article  CAS  PubMed  Google Scholar 

  • Beyaert R, Van Loo G, Heyninck K, Vandenabeele P . (2002). Signaling to gene activation and cell death by tumor necrosis factor receptors and Fas. Int Rev Cytol 214: 225–272.

    Article  CAS  PubMed  Google Scholar 

  • Bezzi M, Hasmim M, Bieler G, Dormond O, Ruegg C . (2003). Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt. J Biol Chem 278: 43603–43614.

    Article  CAS  PubMed  Google Scholar 

  • Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U . (1995). Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science 267: 1485–1488.

    Article  CAS  PubMed  Google Scholar 

  • Burow ME, Weldon CB, Melnik LI, Duong BN, Collins-Burow BM, Beckman BS et al. (2000). PI3-K/AKT regulation of NF-kappaB signaling events in suppression of TNF-induced apoptosis. Biochem Biophys Res Commun 271: 342–345.

    Article  CAS  PubMed  Google Scholar 

  • Byzova TV, Goldman CK, Pampori N, Thomas KA, Bett A, Shattil SJ et al. (2000). A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol Cell 6: 851–860.

    CAS  PubMed  Google Scholar 

  • Cai Z, Korner M, Tarantino N, Chouaib S . (1997). IkappaB alpha overexpression in human breast carcinoma MCF7 cells inhibits nuclear factor-kappaB activation but not tumor necrosis factor-alpha-induced apoptosis. J Biol Chem 272: 96–101.

    Article  CAS  PubMed  Google Scholar 

  • Chen JX, Chen Y, DeBusk L, Lin W, Lin PC . (2004). Dual functional roles of Tie-2/angiopoietin in TNF-alpha-mediated angiogenesis. Am J Physiol Heart Circ Physiol 287: H187–H195.

    Article  CAS  PubMed  Google Scholar 

  • Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T . (1995). Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J 9: 899–909.

    Article  CAS  PubMed  Google Scholar 

  • Corada M, Mariotti M, Thurston G, Smith K, Kunkel R, Brockhaus M et al. (1999). Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo. Proc Natl Acad Sci USA 96: 9815–9820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dechantsreiter MA, Planker E, Matha B, Lohof E, Holzemann G, Jonczyk A et al. (1999). N-Methylated cyclic RGD peptides as highly active and selective alpha(V)beta(3) integrin antagonists. J Med Chem 42: 3033–3040.

    Article  CAS  PubMed  Google Scholar 

  • Fornaro M, Plescia J, Chheang S, Tallini G, Zhu YM, King M et al. (2003). Fibronectin protects prostate cancer cells from tumor necrosis factor-alpha-induced apoptosis via the AKT/survivin pathway. J Biol Chem 278: 50402–50411.

    Article  CAS  PubMed  Google Scholar 

  • Gooch JL, Herrera RE, Yee D . (2000). The role of p21 in interferon gamma-mediated growth inhibition of human breast cancer cells. Cell Growth Differ 11: 335–342.

    CAS  PubMed  Google Scholar 

  • Gourlay CW, Ayscough KR . (2005). The actin cytoskeleton: a key regulator of apoptosis and ageing? Nat Rev Mol Cell Biol 6: 583–589.

    Article  CAS  PubMed  Google Scholar 

  • Hermann C, Assmus B, Urbich C, Zeiher AM, Dimmeler S . (2000). Insulin-mediated stimulation of protein kinase Akt: a potent survival signaling cascade for endothelial cells. Arterioscler Thromb Vasc Biol 20: 402–409.

    Article  CAS  PubMed  Google Scholar 

  • Imose M, Nagaki M, Naiki T, Osawa Y, Brenner DA, Asano T et al. (2003). Inhibition of nuclear factor kappaB and phosphatidylinositol 3-kinase/Akt is essential for massive hepatocyte apoptosis induced by tumor necrosis factor alpha in mice. Liver Int 23: 386–396.

    Article  CAS  PubMed  Google Scholar 

  • Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J . (1997). Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J 16: 2783–2793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim AH, Yano H, Cho H, Meyer D, Monks B, Margolis B et al. (2002). Akt1 regulates a JNK scaffold during excitotoxic apoptosis. Neuron 35: 697–709.

    Article  CAS  PubMed  Google Scholar 

  • Korff T, Augustin HG . (1998). Integration of endothelial cells in multicellular spheroids prevents apoptosis and induces differentiation. J Cell Biol 143: 1341–1352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laird SM, Graham A, Paul A, Gould GW, Kennedy C, Plevin R . (1998). Tumour necrosis factor stimulates stress-activated protein kinases and the inhibition of DNA synthesis in cultures of bovine aortic endothelial cells. Cell Signal 10: 473–480.

    Article  CAS  PubMed  Google Scholar 

  • Lejeune FJ, Lienard D, Matter M, Ruegg C . (2006). Efficiency of recombinant human TNF in human cancer therapy. Cancer Immun 6: 6.

    PubMed  Google Scholar 

  • Mareel M, Dragonetti C, Tavernier J, Fiers W . (1988). Tumor-selective cytotoxic effects of murine tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma) in organ culture of B16 melanoma cells and heart tissue. Int J Cancer 42: 470–473.

    Article  CAS  PubMed  Google Scholar 

  • Meredith Jr J, Fazeli B, Schwartz MA . (1993). The extracellular matrix as a cell survival factor. Mol Biol Cell 4: 953–961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nolop KB, Ryan US . (1990). Enhancement of tumor necrosis factor-induced endothelial cell injury by cycloheximide. Am J Physiol 259: L123–L129.

    CAS  PubMed  Google Scholar 

  • Papapetropoulos A, Fulton D, Mahboubi K, Kalb RG, O’Connor DS, Li F et al. (2000). Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J Biol Chem 275: 9102–9105.

    Article  CAS  PubMed  Google Scholar 

  • Pober JS . (1998). Activation and injury of endothelial cells by cytokines. Pathol Biol (Paris) 46: 159–163.

    CAS  Google Scholar 

  • Rüegg C, Yilmaz A, Bieler G, Bamat J, Chaubert P, Lejeune FJ . (1998). Evidence for the involvement of endothelial cell integrin alpha-v-beta-3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nat Med 4: 408–414.

    Article  PubMed  Google Scholar 

  • Scanlon M, Laster SM, Wood JG, Gooding LR . (1989). Cytolysis by tumor necrosis factor is preceded by a rapid and specific dissolution of microfilaments. Proc Natl Acad Sci USA 86: 182–186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shyy JY, Chien S . (2002). Role of integrins in endothelial mechanosensing of shear stress. Circ Res 91: 769–775.

    Article  CAS  PubMed  Google Scholar 

  • Spagnuolo R, Corada M, Orsenigo F, Zanetta L, Deuschle U, Sandy P et al. (2004). Gas1 is induced by VE-cadherin and vascular endothelial growth factor and inhibits endothelial cell apoptosis. Blood 103: 3005–3012.

    Article  CAS  PubMed  Google Scholar 

  • Suk K, Kim S, Kim YH, Kim KA, Chang I, Yagita H et al. (2001). IFN-gamma/TNF-alpha synergism as the final effector in autoimmune diabetes: a key role for STAT1/IFN regulatory factor-1 pathway in pancreatic beta cell death. J Immunol 166: 4481–4489.

    Article  CAS  PubMed  Google Scholar 

  • Surapisitchat J, Hoefen RJ, Pi X, Yoshizumi M, Yan C, Berk BC . (2001). Fluid shear stress inhibits TNF-alpha activation of JNK but not ERK1/2 or p38 in human umbilical vein endothelial cells: inhibitory crosstalk among MAPK family members. Proc Natl Acad Sci USA 98: 6476–6481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thorburn A . (2004). Death receptor-induced cell killing. Cell Signal 16: 139–144.

    Article  CAS  PubMed  Google Scholar 

  • Yilmaz A, Bieler G, Spertini O, Lejeune FJ, Ruegg C . (1998). Pulse treatment of human vascular endothelial cells with high doses of tumor necrosis factor and interferon-gamma results in simultaneous synergistic and reversible effects on proliferation and morphology. Int J Cancer 77: 592–599.

    Article  CAS  PubMed  Google Scholar 

  • Zhang R, Luo D, Miao R, Bai L, Ge Q, Sessa WC et al. (2005). Hsp90-Akt phosphorylates ASK1 and inhibits ASK1-mediated apoptosis. Oncogene 24: 3954–3963.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs G Adolf, C Buckley, J Downward, Ch Esslinger, B Hemmings and A Jonczyk for reagents and R Driscoll for critical reading of this paper. This work was supported by the Molecular Oncology Program of the National Centre for Competence in Research (NCCR), a research instrument of the Swiss National Science Foundation, the Swiss National Science Foundation (31-63752.00 and 3100AO-105676 to CR), Oncosuisse (OCS-01485-02-2004), the MEDIC foundation and the Fondazione San Salvatore.

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Author notes

  1. M Ameyar

    Present address: 5Current address: Lwoff Institute CNRS FRE 2944, 7 Rue Guy Moquet, F-94801 Villejuif, France,

Authors and Affiliations

  1. Division of Experimental Oncology, Lausanne Cancer Centre, Epalinges, Switzerland

    G Bieler, M Hasmim, Y Monnier, N Imaizumi, L Ponsonnet, F Lejeune & C Rüegg

  2. Swiss Institute for Experimental Cancer Research (ISREC), NCCR Molecular Oncology, Epalinges, Switzerland

    G Bieler, Y Monnier, N Imaizumi, J Bamat & C Rüegg

  3. INSERM UNIT U487, Institut Gustave-Roussy, Villejuif, France

    M Ameyar & S Chouaib

  4. Preclinical Research Oncology, Merck KGaA, Darmstadt, Germany

    M Grell & S L Goodman

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Correspondence to C Rüegg.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Bieler, G., Hasmim, M., Monnier, Y. et al. Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-κB activation and endothelial cell survival. Oncogene 26, 5722–5732 (2007). https://doi.org/10.1038/sj.onc.1210354

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