Cxcl10 Chemokine Induces Migration of ING4-Deficient Breast Cancer Cells via a Novel Cross Talk Mechanism between the Cxcr3 and Egfr Receptors

Emily Tsutsumi, Jeremiah Stricklin, Emily A. Peterson, Joyce A. Schroeder, Suwon Kim

Research output: Contribution to journalArticlepeer-review

Abstract

The chemokine Cxcl10 has been associated with poor prognosis in breast cancer, but the mechanism is not well understood. Our previous study has shown that CXCL10 was repressed by the ING4 tumor suppressor, suggesting a potential inverse functional relationship. We thus investigated a role for Cxcl10 in the context of ING4 deficiencies in breast cancer. We first analyzed public gene expression data sets and found that patients with CXCL10-high/ING4-low expressing tumors had significantly reduced disease-free survival in breast cancer. In vitro, Cxcl10 induced migration of ING4-deleted breast cancer cells but not of ING4-intact cells. Using inhibitors, we found that Cxcl10-induced migration of ING4-deleted cells required Cxcr3, Egfr, and the Gbg subunits downstream of Cxcr3 but not Gai. Immunofluorescent imaging showed that Cxcl10 induced early transient colocalization between Cxcr3 and Egfr in both ING4-intact and ING4-deleted cells, which recurred only in ING4-deleted cells. A peptide agent that binds to the internal juxtamembrane domain of Egfr inhibited Cxcr3/Egfr colocalization and cell migration. Taken together, these results presented a novel mechanism of Cxcl10 that elicits migration of ING4-deleted cells, in part by inducing a physical or proximal association between Cxcr3 and Egfr and signaling downstream via Gbg. These results further indicated that ING4 plays a critical role in the regulation of Cxcl10 signaling that enables breast cancer progression.

Original languageEnglish (US)
Article numbere00382
JournalMolecular and cellular biology
Volume42
Issue number2
DOIs
StatePublished - Feb 2022
Externally publishedYes

Keywords

  • Breast cancer
  • CXCL10 chemokine
  • CXCR3 G protein-coupled receptor
  • Cell migration
  • Egfr
  • ING4 tumor suppressor

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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