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  • Title: G protein‑mediated EGFR transactivation is a common mechanism through which the CXCL12 receptors, CXCR4 and CXCR7, control human cancer cell migration.
    Author: Zieger-Naumann K, Kuhl F, Engele J.
    Journal: Oncol Rep; 2024 Feb; 51(2):. PubMed ID: 38099418.
    Abstract:
    C‑X‑C motif chemokine 12 (CXCL12) promotes metastasis of several tumors by affecting cell migration and invasion via its receptors, C‑X‑C 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 CXCL12‑dependent chemotaxis of A549, C33A, DLD‑1, MDA‑MB‑231 and PC‑3 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 CXCL12‑induced migration of A549, C33A, DLD‑1, MDA‑MB‑231 and PC‑3 cells was attenuated by the Gαi/o‑inhibitor pertussis toxin (PTX), but was unaffected by small interfering RNA‑mediated gene silencing of β‑arrestin1/2. In particular, the sensitivity of DLD‑1 migration to PTX was unexpected, as it is solely dependent on the non‑classical chemokine receptor, CXCR7. Furthermore, chemotactic responses to CXCL12 were additionally prevented by inhibiting EGFR activity via AG1478 and Src kinase activity via Src inhibitor‑1. In conclusion, the results of the present study suggest that G protein‑ and Src‑dependent transactivation of EGFR is a common mechanism through which CXCL12‑bound CXCR4 and/or CXCR7 control cancer cell migration and metastasis. These findings highlight EGFR as a potential therapeutic target that interferes with CXCL12‑induced cancer expansion.
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