Cysteine (C)-X-C Receptor 4 Undergoes Transportin 1-Dependent Nuclear Localization and Remains Functional at the Nucleus of Metastatic Prostate Cancer Cells

被引:53
作者
Don-Salu-Hewage, Ayesha S. [1 ,2 ]
Chan, Siu Yuen [3 ]
McAndrews, Kathleen M. [3 ]
Chetram, Mahandranauth A. [1 ,2 ]
Dawson, Michelle R. [4 ]
Bethea, Danaya A. [1 ]
Hinton, Cimona V. [1 ]
机构
[1] Clark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA
[2] Clark Atlanta Univ, Dept Biol Sci, Atlanta, GA 30314 USA
[3] Univ Hong Kong, Queen Mary Hosp, Dept Paediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R China
[4] Georgia Inst Technol, Sch Chem & Biomol Engn, Atlanta, GA 30332 USA
来源
PLOS ONE | 2013年 / 8卷 / 02期
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
PROTEIN-COUPLED RECEPTORS; HETEROTRIMERIC G-PROTEIN; LYMPH-NODE METASTASIS; CXCR4; EXPRESSION; VENTRICULAR MYOCYTES; BREAST-CANCER; GROWTH-FACTOR; SUBCELLULAR-DISTRIBUTION; CHEMOKINE RECEPTORS; CARDIAC MYOCYTES;
D O I
10.1371/journal.pone.0057194
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 Transportin beta 1 and Transportin beta 1-binding to CXCR4 promoted its nuclear translocation. Importantly, G(alpha i) 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.
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页数:15
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