RESUMO
CXC motif chemokine 12 (CXCL12) promotes metastasis of several tumors by affecting cell migration and invasion via its receptors, CXC chemokine receptor type (CXCR)4 and CXCR7. Current therapeutic approaches focus on the selective inactivation of either CXCR4 or CXCR7 in patients with cancer. Alternative strategies may emerge from the analysis of downstream events that mediate the migratory effects of CXCL12 in cancer cells. While CXCR4 activates cell signaling through both G proteins and arrestins, CXCR7 is believed to preferentially signal through arrestins. The present study analyzed the CXCL12dependent chemotaxis of A549, C33A, DLD1, MDAMB231 and PC3 cells, in which either the activity of G proteins, EGFR or Src kinase was inhibited pharmacologically or the expression of arrestins was inhibited by RNA interference. The results demonstrated that CXCL12induced migration of A549, C33A, DLD1, MDAMB231 and PC3 cells was attenuated by the Gαi/oinhibitor pertussis toxin (PTX), but was unaffected by small interfering RNAmediated gene silencing of ßarrestin1/2. In particular, the sensitivity of DLD1 migration to PTX was unexpected, as it is solely dependent on the nonclassical chemokine receptor, CXCR7. Furthermore, chemotactic responses to CXCL12 were additionally prevented by inhibiting EGFR activity via AG1478 and Src kinase activity via Src inhibitor1. In conclusion, the results of the present study suggest that G protein and Srcdependent transactivation of EGFR is a common mechanism through which CXCL12bound CXCR4 and/or CXCR7 control cancer cell migration and metastasis. These findings highlight EGFR as a potential therapeutic target that interferes with CXCL12induced cancer expansion.