Abstract 3025: CXCR4 is expressed in the nucleus of metastatic prostate cancer cells

Abstract

Abstract Most prostate cancer-related deaths are due to the advancement of the tumor to a metastatic disease. The C-X-C Chemokine Receptor 4 (CXCR4) is a G-protein coupled receptor (GPCR) involved in the metastasis of various cancers, including the prostate. CXCR4 is generally regarded as a plasma membrane receptor; the canon concept of GPCR signaling holds that receptors located at the plasma membrane respond to secreted agonist stimulation. GPCRs, however, have also been observed at other intracellular organelles, including the nuclear membrane. Several cancer models have positively observed expression of a nuclear form of CXCR4 in advanced stage tissues and tumors with a poor prognosis. The significance of these receptors having a dualistic localization pattern is that nuclear receptors can escape from chemotherapy, since most therapeutics are hydrophobic small molecules targeted towards membrane bound receptors, which cannot pass through non-polar regions of the plasma membrane. An initial search of the CXCR4 sequence through the PredictNLS software program revealed a putative, nontraditional nuclear localization sequence, RPRK. We probed prostate cancer tissues for CXCR4 and observed a higher nuclear expression in high grade prostate tumors, compared to low grade, and no detectable CXCR4 in normal human prostate tissue by immunohistochemistry. Subcellular fractionations of prostate cancer cell lines (PC3, DU145 and 22RV1) and normal prostate epithelial cells (RWPE1) demonstrated positive expression of CXCR4 in both nuclear and cytoplasmic fractions, which were confirmed by immunocytochemistry analysis, independent of exogenous SDF1α stimulation. Based on our results, we suggest that CXCR4 is alternately expressed in the nucleus of advanced prostate cancer, which may enhance prostate cancer metastasis. To determine the origin of nuclear CXCR4, the a kinetic localization study confirmed that CXCR4 translocates to the nucleus from the plasma membrane at 37°C, which was inhibited when the same reaction was performed at 4°C. In conclusion, expression and localization of a nuclear CXCR4 may contribute to the advancement of prostate cancer to a metastatic disease, and aid tumors in escaping from therapy. Our studies will contribute to the development of therapeutics towards CXCR4, as current options are targeted towards membrane receptors, which may be ineffective if CXCR4 located and functional inside of the cell. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3025. doi:1538-7445.AM2012-3025