title: Bryostatin-5 blocks stromal cell-derived factor-1 induced chemotaxis via desensitization and down-regulation of cell surface CXCR4 receptors.
abstract: The chemokine receptor CXCR4 and its ligand, stromal cell-derived factor-1 (SDF-1), play important roles in hematopoiesis regulation, lymphocyte activation, and trafficking, as well as in developmental processes, including organogenesis, vascularization, and embryogenesis. The receptor is also involved in HIV infection and tumor growth and metastasis. Antagonists of CXCR4 have been widely evaluated for drugs against HIV and tumors. In an effort to identify novel CXCR4 antagonists, we screened a small library of compounds derived from marine organisms and found bryostatin-5, which potently inhibits chemotaxis induced by SDF-1 in Jurkat cells. Bryostatin-5 is a member of the macrolactones, and its analogue bryostatin-1 is currently being evaluated in clinical trials for its chemotherapeutic potential. The involvement of bryostatins in the SDF-1/CXCR4 signaling process has never been reported. In this study, we found that bryostatin-5 potently inhibits SDF-1-induced chemotaxis but does not affect serum-induced chemotaxis. Further studies indicate that this inhibitory effect is not due to receptor antagonism but rather to bryostatin-5-induced receptor desensitization and down-regulation of cell surface CXCR4. We also show that these effects are mediated by the activation of conventional protein kinase C.
authors.affiliation: National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Graduate University of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xing
authors.initials: X
authors.lastname: He
authors.forename: Liyan
authors.initials: L
authors.lastname: Fang
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.forename: Yanghua
authors.initials: Y
authors.lastname: Yi
authors.forename: Shuyu
authors.initials: S
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054713:Bryostatins / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation / Q000187:drug effects*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008856:Microscopy, Fluorescence; D011493:Protein Kinase C / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000502:physiology*
chemical_list: D054713:Bryostatins; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C078062:bryostatin 5; D011493:Protein Kinase C; D002118:Calcium