CCR9‐mediated signaling through β‐catenin and identification of a novel CCR9 antagonist

Abstract

Elevated levels of chemokine receptor CCR9 expression in solid tumors may contribute to poor patient prognosis. In this study, we characterized a novel CCR9-mediated pathway that promotes pancreatic cancer cell invasion and drug resistance, indicating that CCR9 may play a critical role in cancer progression through activation of β-catenin. We noted that the CCL25/CCR9 axis in pancreatic cancer cells induced the activation of β-catenin, which enhanced cell proliferation, invasion, and drug resistance. CCR9-mediated activation of β-catenin and the resulting downstream effects were effectively inhibited by blockade of the PI3K/AKT pathway, but not by antagonism of Wnt. Importantly, we discovered that CCR9/CCL25 increased the lethal dose of gemcitabine, suggesting decreased efficacy of anti-cancer drugs with CCR9 signaling. Through in silico computational modeling, we identified candidate CCR9 antagonists and tested their effects on CCR9/β-catenin regulation of cell signaling and drug sensitivity. When combined with gemcitabine, it resulted in synergistic cytotoxicity. Our results show that CCR9/β-catenin signaling enhances pancreatic cancer invasiveness and chemoresistance, and may be a highly novel therapeutic target.

Role of chemokine receptors and intestinal epithelial cells in the mucosal inflammation and tolerance

“…In mild to severe UC and CD, patients were shown to have increased numbers of CD14 + HLA-DR hi monocytes in the blood, and these cells express CCR9 and proinflammatory cytokine TNF-a [84]. The binding of CCL25 to CCR9 modulates b-catenin and leads to activation of the PI3K/ Akt signaling pathway [85]. CCR9 expresses on less activated/ mature plasmacytoid DCs and drives its migration into the gut [86].…”

92R Monoclonal Antibody Inhibits Human CCR9+ Leukemia Cells Growth in NSG Mice Xenografts

“…Overexpression of homeostatic chemokine receptors in tumor cells is linked to cancer progression, metastasis, and poor prognosis ( 22 ). Many reports describe a relevant role for the CCL25/CCR9 axis in cancer progression ( 26 , 30 ), in particular, CCR9 expression has been associated with leukemia aggressiveness ( 17 ), its aberrant expression has been detected in several solid tumors ( 14 , 15 , 17 – 30 , 40 ) and has been associated in organ selective metastasis of melanoma to small intestine ( 14 – 16 ), suggesting its potential as a target for cancer treatment. In this context, we have described the generation and characterization of mAb 91R, which inhibits CCR9 + -tumor growth on in vivo subcutaneous xenografts of human ALL in immunodeficient Rag2 −/− mice.…”

Solvent-driven structural topology involving energetically significant intra- and intermolecular chelate ring contacts and anticancer activities of Cu(ii) phenanthroline complexes involving benzoates: experimental and theoretical studies

“…80,81 The receptors (cancer target proteins) used in the present study are highly expressed and closely involved at various stages of cell proliferations which eventually leads to propagation and invasion of cancer cells. [82][83][84][85] Docking was validated by redocking (Fig. 18).…”

“…Docking of compounds 1 and 2 in the active sites of B-RAF kinase, PI3K-gamma receptors, CC chemokine receptor and EGFR kinase domain have been determined since these cancer targets proteins are over-expressed in multiple cancer types such as melanoma, colorectal, thyroid, non-small cell lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, large B cell lymphoma, colon, brain, gastric, breast, bladder cancer and glioblastoma. [82][83][84][85] Moreover, these receptors are attractive targets for the diagnosis and treatment of various cancers. 83,84 The docking studies revealed that compound 2 docked in the active site of all the target proteins with signicant higher docking scores by virtue of hydrogen bonds (B-RAF kinase: CYS532, CYS532; CC chemokine receptor: PHE324, ARG323; EGFR kinase domain: ASP855, LYS745, ARG841 and PI3Kgamma receptors: ASP964, TYR867) and it was further validated by docking their respective standard inhibitors in the active site (Fig.…”