Journal
CANCER SCIENCE
Volume 108, Issue 5, Pages 1049-1057Publisher
WILEY
DOI: 10.1111/cas.13218
Keywords
CDCP1; chemical screening; metastasis; PKC delta; Src
Categories
Funding
- Japan Society for the Promotion of Science [KAKENHI19350031]
- Japan Agency for Medical Research and Development (P-Direct)
- Pancreas Research Foundation of Japan
- Grants-in-Aid for Scientific Research [15K06850, 16K14616, 16K14622, 26290043] Funding Source: KAKEN
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CUB domain-containing protein-1 (CDCP1) is a trans-membrane protein predominantly expressed in various cancer cells and involved in tumor progression. CDCP1 is phosphorylated at tyrosine residues in the intracellular domain by Src family kinases and recruits PKC to the plasma membrane through tyrosine phosphorylation-dependent association with the C2 domain of PKC delta, which in turn induces a survival signal in an anchorage-independent condition. In this study, we used our cell-free screening system to identify a small compound, glycoconjugated palladium complex (Pd-Oqn), which significantly inhibited the interaction between the C2 domain of PKC delta and phosphorylated CDCP1. Immunoprecipitation assays demonstrated that Pd-Oqn hindered the intercellular interaction of phosphorylated CDCP1 with PKC delta and also suppressed the phosphorylation of PKC but not that of ERK or AKT. In addition, Pd-Oqn inhibited the colony formation of gastric adenocarcinoma 44As3 cells in soft agar as well as their invasion. In mouse models, Pd-Oqn markedly reduced the peritoneal dissemination of gastric adenocarcinoma cells and the tumor growth of pancreatic cancer orthotopic xenografts. These results suggest that the novel compound Pd-Oqn reduces tumor metastasis and growth by inhibiting the association between CDCP1 and PKC delta thus potentially representing a promising candidate among therapeutic reagents targeting protein-protein interaction.
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