Cell and Tissue Research

, Volume 342, Issue 1, pp 87–96 | Cite as

TIMP-1 interaction with αvβ3 integrin confers resistance to human osteosarcoma cell line MG-63 against TNF-α-induced apoptosis

  • Ioanna Tsagaraki
  • Effie C. Tsilibary
  • Athina K. Tzinia
Regular Article


Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine affecting diverse cellular responses. TNF-α is cytotoxic in many systems, but it can also act as an anti-apoptotic signal to promote cell survival pathways activated through integrins and extracellular matrix components. This is particularly evident in cancer cells. To unravel the basis of resistance to TNF-α-induced apoptosis, human osteosarcoma MG-63 cell line was used. Our data showed that resistance to apoptosis was accompanied by high levels of TIMP-1 expression in part mediated by NF-κB activation, whereas under apoptotic conditions, in the presence of cycloheximide (CHX), TIMP-1 and αvβ3 integrin protein levels were significantly reduced. Silencing TIMP-1 using siRNA led to increased apoptosis following treatment with TNF-α, whereas exogenously-added recombinant TIMP-1 reduced the extent of apoptosis. Immunoprecipitation and confocal microscopy experiments demonstrated that TIMP-1 interacted with αvβ3 integrins. The biological role of this interaction was revealed by the use of echistatin, an antagonist of αvβ3 integrin. In the presence of echistatin, decreased protection against apoptosis by recombinant TIMP-1 was observed.


Tissue inhibitor of metalloproteinases-1 (TIMP-1) Tumour necrosis factor-alpha (TNF-α) Integrins Osteosarcoma cells Extracellular matrix (ECM) 



The authors thank Dr. Marina Sagnou for her expert assistance with confocal microscopy experiments and Drs. Dimitris Kletsas and Harris Pratsinis for their useful discussions.


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Ioanna Tsagaraki
    • 1
  • Effie C. Tsilibary
    • 1
  • Athina K. Tzinia
    • 1
  1. 1.Institute of BiologyNational Center for Scientific Research “Demokritos”AthensGreece

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