Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways. Proc Natl Acad Sci U S A 2011 Oct 25;108(43):17655-60
Date
10/13/2011Pubmed ID
21990345Pubmed Central ID
PMC3203819DOI
10.1073/pnas.1101133108Scopus ID
2-s2.0-80055081893 (requires institutional sign-in at Scopus site) 190 CitationsAbstract
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.
Author List
Drury LJ, Ziarek JJ, Gravel S, Veldkamp CT, Takekoshi T, Hwang ST, Heveker N, Volkman BF, Dwinell MBAuthors
Michael B. Dwinell PhD Center Director, Professor in the Microbiology and Immunology department at Medical College of WisconsinBrian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
ActinsAnimals
Arrestins
Calcium
Cell Line, Tumor
Cell Movement
Chemokine CXCL12
Colorectal Neoplasms
Cyclic AMP
Dimerization
Flow Cytometry
Humans
Mice
Neoplasm Metastasis
Nuclear Magnetic Resonance, Biomolecular
Receptors, CXCR4
Signal Transduction
beta-Arrestin 2
beta-Arrestins
