Novel small molecule inhibiting CDCP1‐PKCδ pathway reduces tumor metastasis and proliferation

Abstract

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 PKCδ to the plasma membrane through tyrosine phosphorylation‐dependent association with the C2 domain of PKCδ, 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 PKCδ and phosphorylated CDCP1. Immunoprecipitation assays demonstrated that Pd‐Oqn hindered the intercellular interaction of phosphorylated CDCP1 with PKCδ and also suppressed the phosphorylation of PKCδ 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 PKCδ, thus potentially representing a promising candidate among therapeutic reagents targeting protein–protein interaction.

Src Kinase Is Biphosphorylated at Y416/Y527 and Activates the CUB-Domain Containing Protein 1/Protein Kinase C δ Pathway in a Subset of Triple-Negative Breast Cancers

“…74 Targeting either CDCP1 or PKCd directly may be a better therapeutic strategy because CDCP1 knockout mice are viable with no known pathology. 75 Recently, several strategies for inhibiting CDCP1 and/or PKCd have been developed: i) anti-CDCP1 blocking antibodies prevented tissue colonization and caused poly (ADP-ribose) polymerase 1emediated apoptosis in vivo in a mouse metastasis model 61 ; ii) a small molecule blocking the interaction between CDCP1 and PKCd showed promising antitumor effects in mouse models of gastric cancer and pancreatic cancer 76 ; and iii) a CDCP1 blocking fragment that acts extracellularly inhibited CDCP1 dimerization and PKCd activation and decreased tumor progression and metastasis in two mouse models of TNBC. 44,77 Thus, targeting CDCP1 or PKCd directly to inhibit this protumorigenic arm of SFK signaling may prove to be an effective therapeutic strategy for a subset of TNBC patients.…”

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

“…In contrast with these results, recent studies reported that loss of CDCP1, in cells kept in nonadherent conditions, supports tumor cells proliferation by differentially regulating SRC activity (23)(24)(25). Interestingly, CDCP1 targeting, either with monoclonal antibodies or small molecule inhibitors, has demonstrated effectiveness at inhibiting tumor growth and metastasis in vivo (26)(27)(28). Since treatments with either SRC or MAPK inhibitors have been associated with poor tolerability in the clinic (29), CDCP1 targeting could represent an excellent and alternative therapeutic option.…”

Exploring the Role of SRC in Extraocular Muscle Fibrosis of the Graves’ Ophthalmopathy

“…In addition, previous studies showed that the production of a large number of ROS can activate inflammatory signaling pathways like PI3K/Akt/NF-κB, and promote the expression of type I collagen fibers and TGF-β1, ultimately promoting the occurrence of fibrosis (Cohen-Naftaly and Friedman, 2011;Grochot-Przeczek et al, 2012). Interestingly, SRC can positively promote the production of ROS (Nakashima et al, 2017;Walter et al, 2017), and the rise of ROS induced by different stimuli can further promote the activity of SRC in cells (Kopetz et al, 2009). On the contrary, antioxidants can inhibit the activation of SRC activity by inhibiting ROS production (Fu et al, 2014).…”