The IL-8-regulated chemokine receptor CXCR7 stimulates EGFR signaling to promote prostate cancer growth

Rajendra Kumar Singh, Bal L. Lokeshwar

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

The proinflammatory chemokine receptor CXCR7 that binds the ligands CXCL11 and CXCL12 (SDF-1a) is elevated in a variety of human cancers, but its functions are not understood as it does not elicit classical chemokine receptor signaling. Here we report that the procancerous cytokine IL-8 (interleukin-8) upregulates CXCR7 expression along with ligand-independent functions of CXCR7 that promote the growth and proliferation of human prostate cancer cells (CaP cells). In cell culture, ectopic expression or addition of IL-8 selectively increased expression of CXCR7 at the level of mRNA and protein production. Conversely, suppressing IL-8 signaling abolished the ability of IL-8 to upregulate CXCR7. RNAi-mediated knockdown of CXCR7 in CaP cells caused multiple antitumor effects, including decreased cell proliferation, cell-cycle arrest in G1 phase, and decreased expression of proteins involved in G1 to S phase progression. In contrast, addition of the CXCR7 ligand SDF-1a and CXCL11 to CaP cells did not affect cell proliferation. Over expression of CXCR7 in normal prostate cells increased their proliferation in a manner associated with increased levels of phospho-EGFR (epidermal growth factor receptor; pY1110) and phospho-ERK1/2. Notably, coimmunoprecipitation studies established a physical association of CXCR7 with EGFR, linking CXCR7-mediated cell proliferation to EGFR activation. Consistent with these findings, CXCR7-depleted CaP tumors grew more slowly than control tumors, expressing decreased tumor-associated expression of VEGF, cyclin D1, and p-EGFR. Together, these results reveal a novel mechanism of ligand-independent growth promotion by CXCR7 and its coregulation by the proinflammatory factor IL-8 in prostate cancer.

Original languageEnglish
Pages (from-to)3268-3277
Number of pages10
JournalCancer Research
Volume71
Issue number9
DOIs
StatePublished - May 1 2011
Externally publishedYes

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Chemokine Receptors
Interleukin-8
Prostatic Neoplasms
Ligands
Growth
Cell Proliferation
Neoplasms
Up-Regulation
Cyclin D1
G1 Phase
RNA Interference
Cell Cycle Checkpoints
S Phase
Epidermal Growth Factor Receptor
Vascular Endothelial Growth Factor A
Prostate
Proteins
Cell Culture Techniques
Cytokines
Messenger RNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The IL-8-regulated chemokine receptor CXCR7 stimulates EGFR signaling to promote prostate cancer growth. / Singh, Rajendra Kumar; Lokeshwar, Bal L.

In: Cancer Research, Vol. 71, No. 9, 01.05.2011, p. 3268-3277.

Research output: Contribution to journalArticle

Singh, Rajendra Kumar ; Lokeshwar, Bal L. / The IL-8-regulated chemokine receptor CXCR7 stimulates EGFR signaling to promote prostate cancer growth. In: Cancer Research. 2011 ; Vol. 71, No. 9. pp. 3268-3277.
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