Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways

Luke J. Drurya, Joshua J. Ziarek, Steṕhanie Gravel, Christopher T. Veldkamp, Tomonori Takekoshi, Samuel T Hwang, Nikolaus Heveker, Brian F. Volkman, Michael B. Dwinell

Research output: Contribution to journalArticle

127 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)17655-17660
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number43
DOIs
StatePublished - Oct 25 2011
Externally publishedYes

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Keywords

  • Cancer therapeutics
  • Cellular idling
  • Chemokine oligomer
  • Functional selectivity
  • Malignancy

ASJC Scopus subject areas

  • General

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