The IL-8―Regulated Chemokine Receptor CXCR7 Stimulates EGFR Signaling to Promote Prostate Cancer Growth

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-05, Vol.71 (9), p.3268-3277
• Main Authors: RAJENDRA KUMAR SINGH, LOKESHWAR, Bal L
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Cycle - physiology; Cell Growth Processes - physiology; ErbB Receptors - metabolism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Gynecology. Andrology. Obstetrics; Humans; Interleukin-8 - genetics; Interleukin-8 - metabolism; Interleukin-8 - pharmacology; Male; Male genital diseases; Medical sciences; Mice; Mice, Nude; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Phosphorylation; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptors, CXCR - biosynthesis; Receptors, CXCR - genetics; Receptors, CXCR - metabolism; Receptors, CXCR4 - biosynthesis; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Signal Transduction; Tumors; Tumors of the urinary system; Up-Regulation; Urinary tract. Prostate gland
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-2769

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 G(1) phase, and decreased expression of proteins involved in G(1) 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.