title: Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways.
abstract: Chemokines and chemokine receptors are extensively and broadly involved in cancer metastasis. Previously, we demonstrated that epigenetic silencing of the chemokine CXCL12 sensitizes breast and colon cancer cells to endocrine signaling and metastasis to distant tissues. Yet, the precise mechanism whereby CXCL12 production by tumor cells regulates dissemination remains unclear. Here, we show that administration of CXCL12 extended survival of tumor-bearing mice by potently limiting metastasis of colorectal carcinoma or murine melanoma. Because secreted CXCL12 is a mixture of monomeric and dimeric species in equilibrium, oligomeric variants that either promote (monomer) or halt (dimer) chemotaxis were used to dissect the mechanisms interrupting carcinoma metastasis. Monomeric CXCL12 mobilized intracellular calcium, inhibited cAMP signaling, recruited β-arrestin-2, and stimulated filamentous-actin accumulation and cell migration. Dimeric CXCL12 activated G-protein-dependent calcium flux, adenylyl cyclase inhibition, and the rapid activation of ERK1/2, but only weakly, if at all, recruited arrestin, stimulated actin polymerization, or promoted chemotaxis. NMR analyses illustrated that CXCL12 monomers made specific contacts with CXCR4 that were lost following dimerization. Our results establish the potential for inhibiting CXCR4-mediated metastasis by administration of CXCL12. Chemokine-mediated migration and β-arrestin responses did not dictate the antitumor effect of CXCL12. We conclude that cellular migration is tightly regulated by selective CXCR4 signaling evoked by unique interactions with distinct ligand quaternary structures.
authors: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 West Watertown Plank Road, Milwaukee, WI 53214, USA.
authors: Luke J
authors: LJ
authors: Drury
authors: Joshua J
authors: JJ
authors: Ziarek
authors: Stéphanie
authors: S
authors: Gravel
authors: Christopher T
authors: CT
authors: Veldkamp
authors: Tomonori
authors: T
authors: Takekoshi
authors: Samuel T
authors: ST
authors: Hwang
authors: Nikolaus
authors: N
authors: Heveker
authors: Brian F
authors: BF
authors: Volkman
authors: Michael B
authors: MB
authors: Dwinell
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000473:pathology*; D000242:Cyclic AMP / Q000378:metabolism; D019281:Dimerization; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D019906:Nuclear Magnetic Resonance, Biomolecular; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D000199:Actins; C000605258:Arrb2 protein, mouse; D019390:Arrestins; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000242:Cyclic AMP; D002118:Calcium