Abstract
The G-protein coupled receptor (GPCR), Cysteine (C)-X-C Receptor 4 (CXCR4), plays an important role in prostate cancer metastasis. CXCR4 is generally regarded as a plasma membrane receptor where it transmits signals that support transformation, progression and eventual metastasis. Due to the central role of CXCR4 in tumorigenesis, therapeutics approaches such as antagonist and monoclonal antibodies have focused on receptors that exist on the plasma membrane. An emerging concept for G-protein coupled receptors is that they may localize to and associate with the nucleus where they retain function and mediate nuclear signaling. Herein, we demonstrate that CXCR4 associated with the nucleus of malignant prostate cancer tissues. Likewise, expression of CXCR4 was detected in nuclear fractions among several prostate cancer cell lines, compared to normal prostate epithelial cells. Our studies identified a nuclear pool of CXCR4 and we defined a nuclear transport pathway for CXCR4. We reveal a putative nuclear localization sequence (NLS), ‘RPRK’, within CXCR4 that contributed to nuclear localization. Additionally, nuclear CXCR4 interacted with Transportinβ1 and Transportinβ1-binding to CXCR4 promoted its nuclear translocation. Importantly, Gαi immunoprecipitation and calcium mobilization studies indicated that nuclear CXCR4 was functional and participated in G-protein signaling, revealing that the nuclear pool of CXCR4 retained function. Given the suggestion that functional, nuclear CXCR4 may be a mechanism underlying prostate cancer recurrence, increased metastatic ability and poorer prognosis after tumors have been treated with therapy that targets plasma membrane CXCR4, these studies addresses a novel mechanism of nuclear signaling for CXCR4, a novel mechanism of clinical targeting, and demonstrate an active nuclear pool that provides important new information to illuminate what has been primarily clinical reports of nuclear CXCR4.
Highlights
Prostate cancer (PCa) is the second leading cause of increased cancer incidence and cancer-related deaths among men in the United States [1,2]
Muller et al initially described the involvement of chemokine Gprotein coupled receptor (GPCR) receptors in cancer metastasis [19] and Akashi et al reported that the chemokine GPCR, CXCR4, was highly expressed in human malignant PCa compared to normal prostate [20]
PC3 cells were originally isolated from a prostate vertebral metastasis, while DU145 cells were obtained from prostate brain metastasis. 22RV1 cells were from a human prostate carcinoma epithelial cell line derived from a xenograft that was serially propagated in mice, and RWPE1 cells were isolated from normal human prostate epithelium
Summary
Prostate cancer (PCa) is the second leading cause of increased cancer incidence and cancer-related deaths among men in the United States [1,2]. Chemoattractant cytokines (chemokines) enhances the metastatic potential of PCa by binding and activating a family of G-protein coupled receptors (GPCRs) [4,5,6,7] that initiate signals to enhance cell adhesion, invasion and movement, and subsequently, tumor survival at the new site of metastasis. In conventional GPCR signaling, receptors are localized to the PM and influence the activity of PM-localized enzymes, ion channels, and/or second messengers. Their activation by an appropriate ligand triggers signaling through G-protein alpha (Ga) and/or beta-gamma (Gbc) subunits [9], leading to context-dependent outcomes, which may positively and/or negatively regulate the activity of effector molecules in signaling cascades within the cell [10,11]. In conventional CXCR4 signaling, stromal cell-derived factor 1 alpha (SDF1a) is the exclusive ligand for CXCR4 [27], which leads to activation of pathways makes this receptor favorable to tumorigenesis: (i) Gprotein coupled receptor (GPCR) signaling; (ii) PI3K/AKT; (iii)MAPK; (iv) JAK/STAT; (v) Src kinase and (vi) HER2 [28,29,30]
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