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Ribozyme-targeting of a secreted FGF-binding protein (FGF-BP) inhibits proliferation of prostate cancer cells in vitro and in vivo

Oncogene volume 21, pages 5733–5742 (2002)Cite this article

Abstract

Prostate cancer is one of the most common malignant tumors with increasing incidence rates in the aging male. Since locally advanced or metastatic prostate tumors are essentially incurable, identification of new target molecules and treatment strategies is of critical importance. Fibroblast growth factor-2 (FGF-2) acts as potent mitogen which is upregulated in prostate cancers modulating cancer cell proliferation and development of an invasive phenotype. Normally it is tightly bound to the extracellular matrix that quenches its biological activity. The FGF-binding proteins (FGF-BP, HBp17) is a secreted protein which is able to mobilize and activate FGF-2 from the extracellular matrix. Here we show that FGF-BP is highly expressed in prostate tumor cells. To study the functional role of FGF-BP, we use a ribozyme-targeting approach to selectively deplete FGF-BP in prostate cancer cells achieving a more than 50% reduction of FGF-BP mRNA and protein levels in two mass-transfected cell lines. FGF-BP depletion reduces proliferation of the cells in vitro without changes in cell cycle distribution or apoptosis. Using cDNA microarrays, Northern blotting and RT–PCR, we show a complex pattern of changes in the gene expression profiles upon FGF-BP depletion. Most strikingly, ribozyme-mediated reduction of FGF-BP levels completely abolishes the ability of the highly metastatic PC-3 prostate carcinoma cells to grow tumors in an athymic nude mouse in vivo model which is far beyond the effects of FGF-BP ribozyme targeting observed previously in cells from other tumors in the same model. Taken together, our study identifies FGF-BP as a potential rate-limiting factor for prostate cancer growth and, due to its restricted expression pattern in adults, a potentially attractive target for prostate cancer therapy.

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Abbreviations

ECM:

extracellular matrix

EGF:

epithelial growth factor

ELISA:

enzyme-linked immunosorbent assay

ERBIN:

HER-2 interacting protein

FACS:

fluorescence-activated cell sorting

FCS:

fetal calf serum

FGF:

fibroblast growth factor

FGF-BP:

fibroblast growth factor-binding protein

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

GST:

glutathione S-transferase

HRP:

horseradish peroxidase

IL-8:

interleukin-8

PLAB:

placental bone morphogenetic protein

Rz:

ribozyme

SCC:

squamous cell carcinoma

TPA:

12-O-tetradecanoylphorbol-13-acetate

UCHL-1/PGP 9.5:

ubiquitin carboxy-terminal esterase

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Acknowledgements

We are grateful to Andrea Wüstenhagen, Barbara Siegel, Helga Radler and Daniela Wagner for expert technical assistance, to Kirsten Frank for skilful handling of the animals and to Mary-Lou Zuzarte for expert help with cell cycle analysis. This work was supported by grants from the A und E Kulemann-Stiftung and by the Forschungspool of the Philipps-University to A Aigner, and the Deutsche Akademie der Naturforscher Leopoldina (fellowship grant to H Renneberg).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Philipps-University School of Medicine, Marburg, Germany

    Achim Aigner, Jürgen Apel & Frank Czubayko

  2. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Heiner Renneberg & Peter S Nelson

  3. Department of Medicine I, JW Goethe-University, Frankfurt am Main, Germany

    Jörg Bojunga

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  1. Achim Aigner
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Correspondence to Achim Aigner.

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Aigner, A., Renneberg, H., Bojunga, J. et al. Ribozyme-targeting of a secreted FGF-binding protein (FGF-BP) inhibits proliferation of prostate cancer cells in vitro and in vivo. Oncogene 21, 5733–5742 (2002). https://doi.org/10.1038/sj.onc.1205560

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