CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo
Abdullah Alajati, … , Johann De Bono, Andrea Alimonti
Abdullah Alajati, … , Johann De Bono, Andrea Alimonti
Published April 6, 2020
Citation Information: J Clin Invest. 2020;130(5):2435-2450. https://doi.org/10.1172/JCI131133.
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Research Article Oncology

CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo

Abstract

The mechanisms by which prostate cancer shifts from an indolent castration-sensitive phenotype to lethal castration-resistant prostate cancer (CRPC) are poorly understood. Identification of clinically relevant genetic alterations leading to CRPC may reveal potential vulnerabilities for cancer therapy. Here we find that CUB domain-containing protein 1 (CDCP1), a transmembrane protein that acts as a substrate for SRC family kinases (SFKs), is overexpressed in a subset of CRPC. Notably, CDCP1 cooperates with the loss of the tumor suppressor gene PTEN to promote the emergence of metastatic prostate cancer. Mechanistically, we find that androgens suppress CDCP1 expression and that androgen deprivation in combination with loss of PTEN promotes the upregulation of CDCP1 and the subsequent activation of the SRC/MAPK pathway. Moreover, we demonstrate that anti-CDCP1 immunoliposomes (anti–CDCP1 ILs) loaded with chemotherapy suppress prostate cancer growth when administered in combination with enzalutamide. Thus, our study identifies CDCP1 as a powerful driver of prostate cancer progression and uncovers different potential therapeutic strategies for the treatment of metastatic prostate tumors.

Authors

Abdullah Alajati, Mariantonietta D’Ambrosio, Martina Troiani, Simone Mosole, Laura Pellegrini, Jingjing Chen, Ajinkya Revandkar, Marco Bolis, Jean-Philippe Theurillat, Ilaria Guccini, Marco Losa, Arianna Calcinotto, Gaston De Bernardis, Emiliano Pasquini, Rocco D’Antuono, Adam Sharp, Ines Figueiredo, Daniel Nava Rodrigues, Jonathan Welti, Veronica Gil, Wei Yuan, Tatjana Vlajnic, Lukas Bubendorf, Giovanna Chiorino, Letizia Gnetti, Verónica Torrano, Arkaitz Carracedo, Laura Camplese, Susumu Hirabayashi, Elena Canato, Gianfranco Pasut, Monica Montopoli, Jan Hendrik Rüschoff, Peter Wild, Holger Moch, Johann De Bono, Andrea Alimonti

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Figure 4

Overexpression of CDCP1 overcomes Pten loss–induced cellular senescence bypassing the SMAD4 barrier through activation of the Src/MAPK/c-Myc axis.

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Overexpression of CDCP1 overcomes Pten loss–induced cellular senescence ...
(A) Representative images of p-HP1γ. Senescence associated-β-galactosidase (SA-β-Gal) and Cyclin D1 staining in the anterior prostates of WT, CDCP1, Ptenpc–/–, and CDCP1 Ptenpc–/– mice. Scale bars: 125 μm. (B) Western blot analysis of p21, Cyclin D1, COUP-TFII, Smad4, and p53 in anterior prostate glands from the indicated genotypes. (C) qRT-PCR analysis of c-Myc, Cyclin D1, COUP-TFII, p21, p27, and p16 expression in prostates from 12- to 16-week-old Ptenpc–/– and CDCP1 Ptenpc–/– mice (n = 3). (D) Western blot analysis of Pten–/– and CDCP1 Pten–/– MEFs treated with saracatinib (100 nM) for 12 hours. (E) Representative images of SA-β-Gal staining in Pte–/– and CDCP1 Pten–/– MEFs treated with saracatinib (100 nM) and DMSO for 12 hours. Scale bars: 125 μm. Bar graph shows the fold change in growth by crystal violet in Pten–/– and CDCP1 Pten–/– MEFs treated with saracatinib (100 nM) or DMSO as control (n = 3). (F) Western blot analysis of Pten–/– and CDCP1 Pten–/– MEFs transfected with si-c-Myc and control si-scramble (si-Ctrl) after 48 hours. (G) Representative images of SA-β-Gal staining in Pten–/– and CDCP1 Pten–/– MEFs transfected with si-c-Myc and si-Ctrl after 48 hours. Scale bars: 125 μm. Bar graph shows the fold change in growth by crystal violet in Pten–/– and CDCP1 Pten–/– MEFs transfected with si-c-Myc and si-Ctrl (n = 3). (H) Schemes of Cyclin D1 and COUP-TFII promoters. qRT-PCR of ChIP-analysis showing the binding of c-Myc to COUP-TFII promoter and c-Myc and Smad4 to Cyclin D1 promoters in Pten–/– and CDCP1 Pten–/– MEFs. Normal mouse IgG serves as negative control (n = 2). Error bars indicate SD. *P < 0.05; **P < 0.01. Statistical test: 2-tailed t test.