Antimetastatic activity of insulin-like growth factor binding protein-3 in lung cancer is mediated by insulin-like growth factor-independent urokinase-type plasminogen activator inhibition

Seung Hyun Oh, Ok Hee Lee, Claudia P. Schroeder, Yun W. Oh, Shi Ke, Hee Jae Cha, Rang Woon Park, Amir Onn, Roy S. Herbst, Chun Li, Ho Young Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Insulin-like growth factor binding protein-3 (IGFBP-3), a major IGF-binding protein in human serum, regulates the growth of non-small cell lung cancer (NSCLC) cells through IGF-dependent and IGF-independent mechanisms. However, the role of IGFBP-3 in lung cancer metastasis is not well known. In the present study, we showed that noncytotoxic doses of adenoviral or recombinant IGFBP-3 significantly decreased the migration and invasion of H1299 and A549 NSCLC cells. Furthermore, treatment of human lung fibroblasts with recombinant IGFBP-3 suppressed their ability to stimulate the invasion of H1299 cells. Overexpression of IGFBP-3 markedly reduced lung metastasis of A549 cells in an experimental animal model system and prolonged the survival time of the animals. Urokinase-type plasminogen activator (uPA) inhibitor treatment or uPA small interfering RNA transfection of A549 and H1299 cells resulted in a significant decrease in invasion. Corresponding ELISA, Western blot, gelatin zymogram, and serniquantitative reverse transcription-PCR analyses revealed that IGFBP-3 reduced the expression of uPA mRNA through IGF-independent mechanisms. The specific role of uPA in anti-invasive activity of IGFBP-3 was further confirmed in NSCLC cells, in which uPA expression/activity was suppressed by the transfection with synthetic small interfering RNA or by the treatment with uPA inhibitor or induced by the infection with an adenoviral vector. IGFBP-3 also decreased the expression/activity of matrix metalloproteinase-2 through IGF-dependent but uPA-independent pathways. Taken together, our data suggest that IGFPB-3 effectively block uPA- and matrix metalloproteinase-2 -stimulated invasion pathways, ultimately reducing lung cancer cell metastasis. Our findings indicate that IGFBP-3 may be a promising anti-invasive and antimetastatic therapeutic agent in lung cancer.

Original languageEnglish
Pages (from-to)2685-2695
Number of pages11
JournalMolecular Cancer Therapeutics
Volume5
Issue number11
DOIs
StatePublished - Nov 2006
Externally publishedYes

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