The metalloproteinase inhibitor TIMP-2 is down-regulated by androgens in LNCaP prostate carcinoma cells

  • Åse Bratland
  • Erlend Ragnhildstveit
  • Kristin Bjørnland
  • Kristin Andersen
  • Gunhild Mari Mælandsmo
  • Øystein Fodstad
  • Fahri Saatcioglu
  • Anne Hansen ReeEmail author


Tissue inhibitors of metalloproteinases (TIMPs) have been shown to perform several biological functions in tumor promotion, principally by their action of inhibiting matrix metalloproteinases (MMPs) at different steps of the metastatic process. In particular, TIMP-2 is involved in a functional complex with the membrane-type 1 (MT1) MMP to convert the secreted MMP-2 progelatinase into the fully active proteolytic enzyme. We used the human, androgen-sensitive prostate carcinoma cell line LNCaP in coculture with the human osteosarcoma cell line OHS to experimentally address the possibility of androgen-dependent regulatory effects on the functional MT1-MMP/TIMP-2/MMP-2 complex upon interaction between prostate carcinoma and osteoblastic cells in metastasis of prostate cancer to bone. In the LNCaP cells a gradual, time-dependent decline in TIMP-2 mRNA expression was observed in the presence of the synthetic androgen analogue R1881 (100 nM), reaching ∼25% of the control level after 48 h of incubation. Consistent with this, the accumulation of secreted TIMP-2 in media from R1881-treated cells was significantly inhibited already after 3 h. Neither MMP-2 gelatinolytic activity nor expression of MT1-MMP was detected in LNCaP cells. In contrast, the OHS cells showed membrane-associated MT1-MMP expression as well as MMP-2 secretion. However, R1881 treatment of the LNCaP/OHS coculture model did not seem to change the overall proteolytic activity of the MT1-MMP/TIMP-2/MMP-2 complex. Hormonal control of TIMP-2 expression in prostate carcinoma cells has not been previously reported, but whether such regulation has any functional role in the development of osteoblastic metastases in prostate cancer is still unclear.

androgens matrix metalloproteinases metastasis prostate carcinoma TIMP-2 


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Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Åse Bratland
    • 1
  • Erlend Ragnhildstveit
    • 2
  • Kristin Bjørnland
    • 3
  • Kristin Andersen
    • 1
  • Gunhild Mari Mælandsmo
    • 1
  • Øystein Fodstad
    • 1
  • Fahri Saatcioglu
    • 2
    • 4
  • Anne Hansen Ree
    • 1
    • 5
    Email author
  1. 1.Department of Tumor BiologyThe Norwegian Radium HospitalOsloNorway
  2. 2.The Biotechnology Center of OsloUniversity of OsloOsloNorway
  3. 3.The National HospitalInstitute for Surgical Research and Surgical DepartmentOsloNorway
  4. 4.Department of BiologyUniversity of OsloOsloNorway
  5. 5.Department of OncologyThe Norwegian Radium HospitalOsloNorway

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