title: Blocking of CDCP1 cleavage in vivo prevents Akt-dependent survival and inhibits metastatic colonization through PARP1-mediated apoptosis of cancer cells.
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.
authors.affiliation: The Cell Biology Department, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: B
authors.initials: B
authors.lastname: Casar
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.forename: M
authors.initials: M
authors.lastname: Iconomou
authors.forename: J D
authors.initials: JD
authors.lastname: Hooper
authors.forename: J P
authors.initials: JP
authors.lastname: Quigley
authors.forename: E I
authors.initials: EI
authors.lastname: Deryugina
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D017209:Apoptosis; D015815:Cell Adhesion Molecules; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D010958:Plasminogen / Q000172:deficiency / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051745:Protein Kinase C-delta / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; C529673:CDCP1 protein, mouse; D015815:Cell Adhesion Molecules; D008562:Membrane Glycoproteins; D010958:Plasminogen; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta; D005341:Fibrinolysin