Beta-Arrestin-2 Regulates Cxcr7mediated Egfr Transactivation And Tumor Cell Proliferation In Prostate Cancer Cells

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAWe have previously shown that the chemokine receptor CXCR7 trans-activates the epidermal growth factor receptor (EGFR) and is implicated in prostate tumor growth. However, the molecular mechanisms of CXCR7 mediated EGFR-trans-activation are not known. In the present work we show that CXCR7 induced EGFR transactivation is independent of EGF-like ligands such as amphiregulin and heparin-bound EGF. Importantly, treatment with pertussis toxin, a known G-protein inhibitor, had no effect on EGFR phosphorylation, indicating that G-protein signaling was not involved in CXCR7 mediated EGFR transactivation. Since CXCR7 is known to signal through β-arrestin-2 in its ligand dependent manner, we evaluated the role of β-arrestin-2 in CXCR7 induced EGFR trans-activation in prostate cancer cells. We used shRNA to stably down regulate β-arrestin-2 in LNCaP cells to evaluate the role of β-arrestin-2 in CXCR7 mediated induction of EGFR and downstream mitogenic signaling such as ERK1/2 and the phosphoinositide 3-kinase/Akt pathway. Interestingly, down regulation of β-arrestin-2 significantly induced phosphorylation of EGFR at Y1110 and Y1068 along with the phosphorylation/activation of ERK and AKT and an induction of proliferation/colony formation in prostate tumor cells. Moreover, shRNA mediated down regulation of β-arrestin-2 resulted in a decrease of p21 which is in accordance with the observed increased proliferation rate. The results of our study suggest that β-arrestin-2 is crucial negative regulator of CXCR7/EGFR signaling and underscore the importance of β-arrestin-2 in regulation of CXCR7/EGFR mediated tumor cell proliferation.Citation Format: Georgios Kallifatidis, Daniel Munoz, Rajendra K. Singh, Bal L. Lokeshwar. β-arrestin-2 regulates CXCR7-mediated EGFR transactivation and tumor cell proliferation in prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4993. doi:10.1158/1538-7445.AM2015-4993