Targeting of CXCR4 by the Naturally Occurring CXCR4 Antagonist EPI-X4 in Waldenström's Macroglobulinemia
Autor: | Vijay P.S. Rawat, Christian Buske, Lisa M. Kaiser, Daniel Tews, Eberhard Hildt, Zachary R. Hunter, Mirja Harms, Mirco Glitscher, Jan Münch, Daniel Sauter |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Cancer Research medicine.drug_class CXCR4 antagonist Endogeny EPI-X4 CXCR4 lcsh:RC254-282 Tyrosine-kinase inhibitor Article Receptors CXCR4 Antagonists and inhibitors 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine immune system diseases hemic and lymphatic diseases medicine ddc:610 Chemistry Waldenstrom macroglobulinemia Macroglobulinemia lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Haematopoiesis 030104 developmental biology Oncology 030220 oncology & carcinogenesis Ibrutinib Waldenström’s Macroglobulinemia B-Zell-Lymphom Cancer cell Cancer research Primäre Makroglobulinämie DDC 610 / Medicine & health |
Zdroj: | Cancers, 13(4):826 Cancers Cancers, Vol 13, Iss 826, p 826 (2021) Volume 13 Issue 4 |
Popis: | CXCR4 expression and downstream signaling have been identified as key factors in malignant hematopoiesis. Thus, up to 40% of all patients with Waldenström’s macroglobulinemia (WM) carry an activating mutation of CXCR4 that leads to a more aggressive clinical course and inferior outcome upon treatment with the Bruton’s tyrosine kinase inhibitor ibrutinib. Nevertheless, little is known about physiological mechanisms counteracting CXCR4 signaling in hematopoietic neoplasms. Recently, the endogenous human peptide EPI-X4 was identified as a natural CXCR4 antagonist that effectively blocks CXCL12-mediated receptor internalization and suppresses the migration and invasion of cancer cells towards a CXCL12 gradient. Here, we demonstrate that EPI-X4 efficiently binds to CXCR4 of WM cells and decreases their migration towards CXCL12. The CXCR4 inhibitory activity of EPI-X4 is accompanied by reduced expression of genes involved in MAPK signaling and energy metabolism. Notably, the anti-WM activity of EPI-X4 could be further augmented by the rational design of EPI-X4 derivatives showing higher binding affinity to CXCR4. In summary, these data demonstrate that a naturally occurring anti-CXCR4 peptide is able to interfere with WM cell behaviour, and that optimized derivatives of EPI-X4 may represent a promising approach in suppressing growth promoting CXCR4 signaling in WM. publishedVersion |
Databáze: | OpenAIRE |
Externí odkaz: |