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Blocking of CDCP1 cleavage in vivo prevents Akt-dependent survival and inhibits metastatic colonization through PARP1-mediated apoptosis of cancer cells

Oncogene volume 31, pages 3924–3938 (2012)Cite this article

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Abstract

The CUB domain-containing protein-1 (CDCP1) is a transmembrane molecule that has recently been implicated in cancer progression. In this study we have established a novel mechanism for initiation of CDCP1-mediated signaling in vivo and demonstrated that specific 135→70-kDa processing of cell-surface CDCP1 by extracellular serine proteases is a prerequisite for CDCP1-dependent survival of cancer cells during metastasis. The in vivo cleavage of CDCP1 triggers a survival program involving recruitment of Src and PKCδ, Src-mediated phosphorylation of cell-surface-retained 70-kDa CDCP1, activation of Akt and suppression of PARP1-induced apoptosis. We demonstrate in vivo that phosphorylated Src, PKCδ and Akt all constitute activated elements of a CDCP1-signaling axis during tissue colonization of tumor cells. Preventing in vivo cleavage of CDCP1 with unique anti-CDCP1 antibodies, serine protease inhibitors or genetic modulation of the cleavage site in the CDCP1 molecule completely abrogated survival signaling associated with the 70-kDa CDCP1, and induced PARP1 cleavage and PARP1-mediated apoptosis, ultimately resulting in substantial inhibition of tissue colonization by tumor cells. The lack of CDCP1 cleavage in the lung tissue of plasminogen-knockout mice along with a coordinated reduction in tumor cell survival in a lung retention model, and importantly rescue of both by in vivo supplied plasmin, indicated that plasmin is the crucial serine protease executing in vivo cleavage of cell-surface CDCP1 during early stages of lung colonization. Together, our findings indicate that in vivo blocking of CDCP1 cleavage upstream from CDCP1-induced pro-survival signaling provides a potential mechanism for therapeutic intervention into metastatic disease.

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Acknowledgements

We thank Drs Frank Castellino and Victoria Ploplis for providing the breeding pair of plasminogen-KO mice. We also thank Dr Lindsey Miles for insightful suggestions, and originally procuring and housing the plasminogen-KO mice. This study was supported by NIH Grants R01 CA 129484 and R01 CA 105412 (to JPQ), NIH/NCRR/STSI Grant RR 025774 (Pilot Award to EID), Postdoctoral Fellowship from the Science and Innovation Ministry of Spain (to BC), and the National Health and Medical Research Council of Australia (Fellowship 339732 to JDH).

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Authors and Affiliations

  1. The Cell Biology Department, The Scripps Research Institute, La Jolla, CA, USA

    B Casar, J P Quigley & E I Deryugina

  2. Mater Medical Research Institute, South Brisbane, Queensland, Australia

    Y He, M Iconomou & J D Hooper

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  1. B Casar
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  2. Y He
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  3. M Iconomou
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Correspondence to E I Deryugina.

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Casar, B., He, Y., Iconomou, M. et al. Blocking of CDCP1 cleavage in vivo prevents Akt-dependent survival and inhibits metastatic colonization through PARP1-mediated apoptosis of cancer cells. Oncogene 31, 3924–3938 (2012). https://doi.org/10.1038/onc.2011.555

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