CUB Domain–Containing Protein 1, a Prognostic Factor for Human Pancreatic Cancers, Promotes Cell Migration and Extracellular Matrix Degradation

Abstract

CUB domain-containing protein 1 (CDCP1) is a membrane protein that is highly expressed in several solid cancers. We reported previously that CDCP1 regulates anoikis resistance as well as cancer cell migration and invasion, although the underlying mechanisms have not been elucidated. In this study, we found that expression of CDCP1 in pancreatic cancer tissue was significantly correlated with overall survival and that CDCP1 expression in pancreatic cancer cell lines was relatively high among solid tumor cell lines. Reduction of CDCP1 expression in these cells suppressed extracellular matrix (ECM) degradation by inhibiting matrix metalloproteinase-9 secretion. Using the Y734F mutant of CDCP1, which lacks the tyrosine phosphorylation site, we showed that CDCP1 regulates cell migration, invasion, and ECM degradation in a tyrosine phosphorylation-dependent manner and that these CDCP1-associated characteristics were inhibited by blocking the association of CDCP1 and protein kinase Cdelta (PKCdelta). CDCP1 modulates the enzymatic activity of PKCdelta through the tyrosine phosphorylation of PKCdelta by recruiting PKCdelta to Src family kinases. Cortactin, which was detected as a CDCP1-dependent binding partner of PKCdelta, played a significant role in migration and invasion but not in ECM degradation of pancreatic cells. These results suggest that CDCP1 expression might play a crucial role in poor outcome of pancreatic cancer through promotion of invasion and metastasis and that molecules blocking the expression, phosphorylation, or the PKCdelta-binding site of CDCP1 are potential therapeutic candidates.

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance

“…In several tumor types that commonly metastasize via vascular routes, including lung, kidney, pancreas and colon cancer, elevated or cell-surface expression of CDCP1 is associated with poor patient outcome. [12][13][14][15][16][17] Consistent with a role in hematogenous metastasis, in animal models of vascular dissemination, survival of cancer cells undergoing extravasation is markedly enhanced by a mechanism involving serine protease cleavage to generate 70 kDa CDCP1. This initiates pro-survival signaling via focal adhesion kinase 1 and phosphoinositide 3-kinase (PI3K) dependent protein kinase B (Akt) activation resulting in suppression of poly (ADP-ribose) polymerase 1 (PARP1) mediated apoptosis.…”

CDCP1 Regulates the Function of MT1-MMP and Invadopodia-Mediated Invasion of Cancer Cells

“…CDCP1 expression is strongly associated with cancer progression and poor prognosis in renal cell carcinoma, lung adenocarcinoma, and pancreatic cancer (8)(9)(10). We previously reported that CDCP1 is a critical regulator of anoikis resistance in lung cancer cells (11), peritoneal dissemination of gastric scirrhous carcinoma (12), and invasion of pancreatic cancer cells (8). We showed that knockdown of CDCP1 resulted in the inhibition of extracellular matrix (ECM) degradation by pancreatic cancer cells (8).…”

“…The expression of CDCP1 was reported in several human malignancies, such as colon and breast cancers (3,7). CDCP1 expression is strongly associated with cancer progression and poor prognosis in renal cell carcinoma, lung adenocarcinoma, and pancreatic cancer (8)(9)(10). We previously reported that CDCP1 is a critical regulator of anoikis resistance in lung cancer cells (11), peritoneal dissemination of gastric scirrhous carcinoma (12), and invasion of pancreatic cancer cells (8).…”

“…We previously reported that CDCP1 is a critical regulator of anoikis resistance in lung cancer cells (11), peritoneal dissemination of gastric scirrhous carcinoma (12), and invasion of pancreatic cancer cells (8). We showed that knockdown of CDCP1 resulted in the inhibition of extracellular matrix (ECM) degradation by pancreatic cancer cells (8). Tyrosine phosphorylation of CDCP1, especially at tyrosine 734 residue, plays an essential role in these oncogenic processes (8,11,12).…”

“…We showed that knockdown of CDCP1 resulted in the inhibition of extracellular matrix (ECM) degradation by pancreatic cancer cells (8). Tyrosine phosphorylation of CDCP1, especially at tyrosine 734 residue, plays an essential role in these oncogenic processes (8,11,12). However, the exact molecular mechanisms by which CDCP1 regulates cancer cell invasion remain to be determined.…”