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

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...

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Published in:	Oncogene Vol. 31; no. 35; pp. 3924 - 3938
Main Authors:	Casar, B, He, Y, Iconomou, M, Hooper, J D, Quigley, J P, Deryugina, E I
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 30-08-2012 Nature Publishing Group
Subjects:	631/80/474 631/80/82/23 631/80/86 692/699/67/322 AKT protein Animal models Animals Antibodies Antigens, Neoplasm - metabolism Apoptosis Cancer Care and treatment Cell activation Cell Biology Cell Line Cell Membrane - metabolism Cell surface Cell survival Colonization Development and progression Female Fibrinolysin - metabolism HEK293 Cells Human Genetics Humans Internal Medicine Kinases Lung Male Medicine Medicine & Public Health Membrane Glycoproteins - metabolism Metastases Metastasis Mice Mice, Knockout Mice, Nude Neoplasm Metastasis Oncology original-article Patient outcomes Phosphorylation Physiological aspects Plasmin Plasminogen - deficiency Plasminogen - genetics Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases - metabolism Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Proteases Protein kinase C Protein Kinase C-delta - metabolism Proteinase inhibitors Proto-Oncogene Proteins c-akt - metabolism Serine Serine proteinase Signal Transduction Src protein src-Family Kinases - metabolism Therapeutic applications Tumor cells United States apoptosis cleavage CDCP1 signaling colonization plasmin
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2011.555