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Lysyl oxidase propeptide inhibits prostate cancer cell growth by mechanisms that target FGF-2-cell binding and signaling

Oncogene volume 28, pages 3390–3400 (2009)Cite this article

Abstract

Enhanced RAS signaling and decreased androgen dependence of prostate cancer cells accompany poor clinical outcomes. Elevated autocrine fibroblast growth factors 2 (FGF-2) signaling promotes prostate cancer cell growth and survival. Expression of lysyl oxidase (LOX) inhibits RAS transforming activity. LOX is secreted as 50 kDa pro-LOX protein and then undergoes extracellular proteolytic processing to form ∼30 kDa LOX enzyme and ∼18 kDa propeptide (LOX-PP). We have previously shown that LOX-PP inhibits breast cancer cell transformation and tumor formation, but mechanisms of action of LOX-PP have not been fully elucidated. Here we report that LOX expression is reduced in prostate cancer cell lines and that recombinant LOX-PP protein inhibits serum-stimulated DNA synthesis and MEK/ERK and PI3K/AKT pathways in DU 145 and PC-3 androgen-independent cell lines. In DU 145 cells, treatment with a pharmacologic FGF-receptor inhibitor or a neutralizing anti-FGFR1 antibody mimicked LOX-PP inhibition of serum-stimulated DNA synthesis. FGF-2-stimulated DNA synthesis, ERK1/2, AKT and FRS2α activation were found all to be inhibited by LOX-PP in DU 145 cells. LOX-PP reduced specific binding of FGF-2 to DU 145 cells, suggesting that LOX-PP targets FGF signaling at the receptor. Interestingly, PC-3 cells did not respond to FGF-2, consistent with previous reports. We conclude that LOX-PP inhibits proliferation of DU 145 cells by interfering with FGFR(s) binding and signaling, and that LOX-PP has other mechanisms of action in PC-3 cells.

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Acknowledgements

This study was supported by NIH/NCI CA082742, DOD Award W81XWH-08-1-0349, NIH/NIDCR DE14066. We thank Danielle Stephens and Emilie Vu for expert preparation of rLOX-PP.

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Authors and Affiliations

  1. Division of Oral Biology, Department of Periodontology and Oral Biology, Boston University Henry M Goldman School of Dental Medicine, Boston, MA, USA

    A H Palamakumbura, S R Vora & P C Trackman

  2. Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA

    M A Nugent, K H Kirsch, G E Sonenshein & P C Trackman

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  1. A H Palamakumbura
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  2. S R Vora
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  3. M A Nugent
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  4. K H Kirsch
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Correspondence to P C Trackman.

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

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Palamakumbura, A., Vora, S., Nugent, M. et al. Lysyl oxidase propeptide inhibits prostate cancer cell growth by mechanisms that target FGF-2-cell binding and signaling. Oncogene 28, 3390–3400 (2009). https://doi.org/10.1038/onc.2009.203

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